UCSF scientist Hana El-Samad receives grant for innovative cell research.

Hana El-Samad, UCLA

To explain her research into the workings of cells, UCSF scientist Hana El-Samad offers an analogy from the world of machines.

“Imagine a telephone or Internet network,” she says. “Despite their staggering complexity, packets of information find their destination on these networks and are interpreted correctly.”

Cells work in networks as well, she says, and information is constantly generated and transduced. A change in temperature of 2 degrees will change the information a cell needs to send to a gene, for instance; a change in the level of, say, glucose, will also change the information.

El-Samad is trying to understand how each change is encoded in the cells, so that it sends the right information to the genes it’s targeting, and then she wants to understand how those genes are able to decode the message.

Her novel approach in this arena won her a $1.4 million grant in February from the Paul G. Allen Family Foundation. The grants are aimed at funding high-risk but potentially high-reward research that is not typically funded by traditional sources.

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UC Irvine study also identifies possible gene target linked to cognitive disabilities.

Marcelo Wood, UC Irvine

UC Irvine neurobiologists have found a novel molecular mechanism that helps trigger the formation of long-term memory. The researchers believe the discovery of this mechanism adds another piece to the puzzle in the ongoing effort to uncover the mysteries of memory and, potentially, certain intellectual disabilities.

In a study led by Marcelo Wood of UC Irvine’s Center for the Neurobiology of Learning & Memory, the team investigated the role of this mechanism – a gene designated Baf53b – in long-term memory formation. Baf53b is one of several proteins making up a molecular complex called nBAF.

Mutations in the proteins of the nBAF complex have been linked to several intellectual disorders, including Coffin-Siris syndrome, Nicolaides-Baraitser syndrome and sporadic autism. One of the key questions the researchers addressed is how mutations in components of the nBAF complex lead to cognitive impairments.

In their study, Wood and his colleagues used mice bred with mutations in Baf53b. While this genetic modification did not affect the mice’s ability to learn, it did notably inhibit long-term memories from forming and severely impaired synaptic function.

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UCLA, Caltech researchers successfully monitor change in genetically modified T cells.

James Heath, UCLA

A new study of genetically modified immune cells by scientists from UCLA and the California Institute of Technology could help improve a promising treatment for melanoma, an often fatal form of skin cancer.

The research, which appears today (March 21) in the advance online edition of the journal Cancer Discovery, was led by James Heath, a member of UCLA’s Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research and UCLA’s Jonsson Comprehensive Cancer Center. Heath is a professor of molecular and medical pharmacology at UCLA and also holds the Elizabeth W. Gilloon Chair in Chemistry at Caltech.

The melanoma treatment uses T cells — immune cells that play a major role in fighting infection — taken from patients with melanoma. The cells are then genetically modified in the laboratory so that when they are reintroduced into a patient’s bloodstream, they specifically attack melanoma tumors. In early clinical trials, this treatment was shown to shrink tumors dramatically in many patients, but the positive effects were often short-lived.

The UCLA and Caltech researchers found that after the engineered T cells were returned to patients, their efficacy faded within two to three weeks. Surprisingly, however, once the engineered cells were no longer effective, a new group of non-engineered T cells arose that had a similar tumor-killing effect that lasted even longer, the scientists discovered.

Using newly developed nanotechnology chips to perform multidimensional and multiplexed immune-monitoring assays, the researchers were able to examine at high resolution single engineered T cells taken at different times from patients undergoing the therapy, each of whom had a different level of response to the treatment.

“The engineered T cells did not recover their tumor-killing effect,” Heath said, “but after one month, another group of T cells appeared that did have tumor-killing effects for another 90 days. Those were not the genetically engineered T cells, and they appeared to be a byproduct of a process called ‘antigen spreading’ by the original engineered cells. After 90 days, those cells lost their tumor-killing ability as well.”

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Cutting-edge research at UC Merced explores benefits of biofilament “deformation.”

Sachin Goval (right) and UC Merced grad students

People don’t often think of deformation as a good thing.

But when it comes to biofilaments – such as strands of DNA – it’s not only good, it’s necessary for the biofilament to complete its functions. When biofilaments twist, twine, bend or loop in the ways that are correct for them, the result is a normal, healthy organism, be it a cell, an organ or a whole body.

Professor Sachin Goyal, with the UC Merced School of Engineering, and graduate student Nitish Appanasamy are modeling the “deformation” of certain biofilaments, trying to find ways to predict how such strands react when proteins, enzymes and outside forces are introduced to them.

The goal is to be able to design medications or medical treatments that will encourage biofilaments to deform in ways that cure diseases.

“In principal, it extends to any disease,” Goyal said. “It could work for injuries, too, because what’s really about is tissue damage. Every disease, every injury involves DNA.”

Goyal’s research is a perfect example of UC Merced’s cutting-edge, interdisciplinary research that could change the way medicine is practiced and applied.

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Targeting small intestine may be new strategy to prevent diet-induced atherosclerosis.

Alan Fogelman, UCLA

UCLA researchers have genetically engineered tomatoes to produce a peptide that mimics the actions of good cholesterol when consumed.

Published in the April issue of the Journal of Lipid Research and featured on the cover, their early study found that mice that were fed these tomatoes in freeze-dried, ground form had less inflammation and plaque build-up in their arteries.

“This is one of the first examples of a peptide that acts like the main protein in good cholesterol and can be delivered by simply eating the plant,” said senior author Dr. Alan M. Fogelman, executive chair of the department of medicine and director of the atherosclerosis research unit at the David Geffen School of Medicine at UCLA. “There was no need to isolate or purify the peptide — it was fully active after the plant was eaten.”

After the tomatoes were eaten, the peptide surprisingly was found to be active in the small intestine but not in the blood, suggesting that targeting the small intestine may be a new strategy to prevent diet-induced atherosclerosis, the plaque-based disease of the arteries that can lead to heart attacks and strokes.

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UCSF faculty member to lead effort to evaluate risks, benefits.

Kathryn Phillips, UCSF

By David Jacobson

Improving technologies are rapidly cutting the cost of whole genome sequencing, a process that reveals the complete library of a patient’s genetic information. Indeed, the era of the $1,000 genome — a catchphrase for the test’s relative affordability — appears imminent.

But will the wider application of this encyclopedic option in personalized medicine help patients and health care providers prevent and more effectively treat diseases, or will it open a Pandora’s Box of confusion, fears, and costly, unnecessary treatments?

UC San Francisco School of Pharmacy faculty member Kathryn Phillips, Ph.D., will lead the first national study to analyze how physicians and patients in the general population, as well as those given whole genome sequencing results in a clinical trial, evaluate the benefits and risks posed by this profusion of genetic information. The project will address questions such as:

• How much do patients want to know?
• How do patients and physicians assess the significance and usefulness of these tests’ myriad potential findings?
• Which findings call for medical intervention versus monitoring?
• What about likely future conditions that currently cannot be treated?

The four-year, $2.4 million project, “Benefit-Risk Tradeoffs for Whole Genome Sequencing,” recently funded by the National Human Genome Research Institute (NHGRI), will also be the first to systematically examine the overall implications of such testing for the health care system and for society.

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Corporation for Education Network Initiatives in California honors UC Santa Cruz’s CGHub.

David Haussler, UC Santa Cruz

The UC Santa Cruz Cancer Genomics Hub (CGHub) has been honored by the Corporation for Education Network Initiatives in California (CENIC) as the recipient of the 2013 Innovations in Networking Award for High-Performance Research Applications.

UCSC has built CGHub, a 5-petabyte database, to store tumor genomes sequenced through National Cancer Institute (NCI) projects. Through this effort, CGHub is tackling the significant computational challenges posed by storing, serving, and interpreting cancer genomics data.

The CGHub mission is to facilitate the work of scientific researchers. It is designed to be a fully automated resource, appearing to the user as an extension of the user’s home institute computing system. Making such vast amounts of data accessible to collaborating researchers nationally and internationally requires advanced networking to allow the research to be carried out as seamlessly as possible.

The project is led by UC Santa Cruz bioinformatics expert David Haussler. Haussler is a distinguished professor of biomolecular engineering in the Baskin School of Engineering at UCSC and a Howard Hughes Medical Institute investigator. “By providing researchers with comprehensive catalogs of the key genomic changes in many major types and subtypes of cancer, these efforts will support the development of more effective ways to diagnose and treat cancer,” Haussler said.

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Elevated levels of antimicrobial lysozyme effective in treating disease in study with pigs.
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Milk from goats that were genetically modified to produce higher levels of a human antimicrobial protein has proved effective in treating diarrhea in young pigs, demonstrating the potential for food products from transgenic animals to one day also benefit human health, report researchers at the University of California, Davis.

The study is the first on record to show that goats’ milk carrying elevated levels of the antimicrobial lysozyme, a protein found in human breast milk, can successfully treat diarrhea caused by bacterial infection in the gastrointestinal tract.

The findings, slated to appear today (March 13) in the online scientific journal PLOS ONE, offer hope that such milk may eventually help prevent human diarrheal diseases that each year claim the lives of 1.8 million children around the world and impair the physical and mental development of millions more.

“Many developing parts of the world rely on livestock as a main source of food,” said James Murray, a UC Davis animal science and veterinary medicine professor and lead researcher on the study. “These results provide just one example that, through genetic engineering, we can provide agriculturally relevant animals with novel traits targeted at solving some of the health-related problems facing these developing communities.”

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UCSF scientists find more precise way to “turn off” genes.

Wendell Lim, UC San Francisco

Scientists at UC San Francisco have found a more precise way to turn off genes, a finding that will speed research discoveries and biotech advances and may eventually prove useful in reprogramming cells to regenerate organs and tissues.

The strategy borrows from the molecular toolbox of bacteria, using a protein employed by microbes to fight off viruses, according to the researchers, who describe the technique in the current issue of Cell.

Turning off genes is a major goal of treatments that target cancer and other diseases. In addition, the ability to turn genes off to learn more about how cells work is a key to unlocking the mysteries of biochemical pathways and interactions that drive normal development as well as disease progression.

“We’ve spent energy and effort to map the human genome, but we don’t yet understand how the genetic blueprint leads to a human being, and how we can manipulate the genome to better understand and treat disease,” said Wendell Lim, Ph.D., a senior author of the study. Lim is director of the UCSF Center for Systems and Synthetic Biology, a Howard Hughes Medical Institute investigator and professor of cellular and molecular pharmacology.

The new technology developed by the team of UCSF and UC Berkeley researchers is called CRISPR interference – not to be confused with RNA interference, an already popular strategy for turning off protein production.

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UCLA researchers find signs of disease decades before illness strikes.

Paul Thompson, UCLA

Scientists at UCLA have discovered a new genetic risk factor for Alzheimer’s disease by screening people’s DNA and then using an advanced type of scan to visualize their brains’ connections.

Alzheimer’s disease, the most common cause of dementia in the elderly, erodes these connections, which we rely on to support thinking, emotion and memory. With no known cure for the disease, the 20 million Alzheimer’s sufferers worldwide lack an effective treatment. And we are all at risk: Our chance of developing Alzheimer’s doubles every five years after age 65.

The UCLA researchers discovered a common abnormality in our genetic code that increases the risk of Alzheimer’s. To find the gene, they used a new imaging method that screens the brain’s connections — the wiring, or circuitry, that communicates information. Switching off such Alzheimer’s risk genes (nine of them have been implicated over the last 20 years) could stop the disorder in its tracks or delay its onset by many years.

The research is published in the March 4 online edition of the journal Proceedings of the National Academy of Sciences.

“We found a change in our genetic code that boosts our risk for Alzheimer’s disease,” said the study’s senior author, Paul Thompson, a UCLA professor of neurology and a member of the UCLA Laboratory of Neuro Imaging. “If you have this variant in your DNA, your brain connections are weaker. As you get older, faulty brain connections increase your risk of dementia.”

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Berkeley Lab researchers produce first step-by-step look at transcription initiation.

Eva Nogales and Yuan He, Berkeley Lab

Researchers with the U.S. Department of Energy’s Lawrence Berkeley National Laboratory have achieved a major advance in understanding how genetic information is transcribed from DNA to RNA by providing the first step-by-step look at the biomolecular machinery that reads the human genome.

“We’ve provided a series of snapshots that shows how the genome is read one gene at a time,” says biophysicist Eva Nogales who led this research. “For the genetic code to be transcribed into messenger RNA, the DNA double helix has to be opened and the strand of gene sequences has to be properly positioned so that RNA polymerase, the enzyme that catalyzes transcription, knows where the gene starts. The electron microscopy images we produced show how this is done.”

Says Paula Flicker of the National Institutes of Health’s National Institute of General Medical Sciences, which partly funded the research, “The process of transcription is essential to all living things so understanding how it initiates is enormously important. This work is a beautiful example of integrating multiple approaches to reveal the structure of a large molecular complex and provide insight into the molecular basis of a fundamental cellular process.”

Nogales, who holds joint appointments with Berkeley Lab, UC Berkeley and the Howard Hughes Medical Institute, is the corresponding author of a paper describing this study in the journal Nature. The paper is titled “Structural visualization of key steps in human transcription initiation.” Co-authors are Yuan He, Jie Fang and Dylan Taatjes.

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Researchers solve puzzle of when ancient canines expanded from Southeast Asia.

Part of the ancient mystery of the makeup of the modern Western dog has been solved by a team led by researchers at the University of California, Davis, School of Veterinary Medicine.

Several thousand years after dogs originated in the Middle East and Europe, some of them moved south with ancient farmers, distancing themselves from native wolf populations and developing a distinct genetic profile that is now reflected in today’s canines.

These findings, based on the rate of genetic marker mutations in the dog’s Y chromosome, supply the missing piece to the puzzle of when ancient dogs expanded from Southeast Asia. The study results are published online this month in the journal Molecular Biology and Evolution.

“Our findings reconcile more than a decade of apparently contradictory archaeological and genetic findings on the geographic origins of the dogs,” said Ben Sacks, lead study author and director of the Canid Diversity and Conservation Group in the Veterinary Genetics Laboratory at the UC Davis School of Veterinary Medicine.

Considerable archaeological evidence indicates that the first dogs appeared about 14,000 years ago in Europe and the Middle East, while dogs did not appear in Southeast Asia until about 7,000 years later. Scientists have been puzzled, though, because growing genetic evidence suggests that modern Western dogs, including modern European dogs, are derived from a Southeast Asian population of dogs that spread throughout the world.

The problem: If dogs originated in Europe, why does genetic evidence suggest that modern European dogs are originally from Southeast Asia? Sacks and his team think they’ve found the answer.

“Data from our study indicate that about 6,000 to 9,000 years ago, during what is known as the Neolithic age, ancient farmers brought dogs south of the Yangtze River, which runs west to east across what is now China,” Sacks said.

“While dogs in other parts of Eurasia continued to readily interbreed with wolves, the dogs that moved into Southeast Asia no longer lived near wolves, and so they developed a totally different evolutionary trajectory, influenced by the agriculture of Southeast Asia,” he said. “Those ancient dogs apparently underwent a significant evolutionary transformation in southern China that enabled them to demographically dominate and largely replace earlier western forms.”

To calculate when the modern European and Southeast Asian dogs diverged, the researchers calculated the mutation rate of genetic markers on the Y chromosome in a sample of 100 Australian dingoes, a dog population known to have appeared about 4,200 years ago. Knowing the rate at which these genetic mutations occur, the researchers were able to backtrack through history and estimate the point when dogs of Eurasia and Southeast Asia parted company as being roughly 7,000 years ago.

“So, in a sense, both of the original hypotheses are true: Dogs did originate in Europe and the Middle East, but modern dogs trace their ancestry most recently to the East and specifically Southeast Asia,” Sacks said.

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