TAG: "Genetics"

A mother’s genes can influence the bacteria in her baby’s gut


Research may have applications for protecting preemies from range of intestinal diseases.

Zachary Lewis (left) and David Mills, UC Davis

By Phyllis Brown, UC Davis

Researchers at UC Davis have found that a gene, which is not active in some mothers, produces a breast milk sugar that influences the development of the community of gut bacteria in their infants. The sugars produced by these mothers, called “secretors,” are not digested by the infant, but instead nourish specific bacteria that colonize their babies’ guts soon after birth.

Mothers known as “non-secretors” have a non-functional fucosyltransferase 2 (FUT2) gene, which alters the composition of their breast milk sugars and changes how the microbial community, or microbiota, of their infants’ guts develop.

The research may have applications in a clinical setting for protecting premature infants from a range of intestinal diseases including necrotizing enterocolitis (NEC), a condition that is the second most common cause of death among premature infants in the United States.

The researchers emphasized that the finding does not suggest that breast milk from mothers without an active copy of the gene is less nourishing or healthy. Rather, it conveys the subtle and elegant choreography of one part of the human microbiome: The relationships between the mothers’ genetics, the composition of her breast milk and the development of their infants’ gut microbiota. It also reveals clues for enriching desirable bacteria in populations at risk of intestinal diseases — such as preemies.

“In no way is the nonsecretor mother’s milk less healthy, and their babies are at no greater risk,” said David Mills, Peter J. Shields Endowed Chair in Dairy Food Science at UC Davis and senior study author. “What this work does show us is that the mother’s genotype matters, and that it influences the breast milk, which clearly drives the establishment of microbes in the intestines of their babies.”

The research examining the differences in infant gut microbial populations arising from differences in human milk oligosaccharides (sugars), “Maternal Fucosyltransferase 2 Status Affects the Gut Bifidobacterial Communities of Breastfed Infants,” is published online today (April 9) in the journal Microbiome, a BioMedCentral journal.

Varieties of Bifidobacterium inhabit the gastrointestinal tracts and mouths of mammals and are one of the major genera of bacteria that make up the microbial community of the infant colon. The relationship between human genetics, breast milk and Bifidobacterium appears to have developed throughout mammalian evolution.

Development of a healthy gut microbiota can have a lifelong effect on health, and early intervention in the establishment of that microbiota could have lifelong positive effects: The early establishment of bifidobacteria has been shown to be associated with improved immune response to vaccines, development of the infants’ immature immune system, and protection against pathogens.

Bifidobacterium are known to consume the 2′-fucosylated glycans (sugars) found in the breast milk of women with the fucosyltransferase 2 mammary gene. The study found that, on average, Bifidobacterium were established earlier and more frequently in infants fed by women with an active copy of the gene, the secretors, than without one, the non-secretors.

The authors found that the intestinal tracts of infants fed by non-secretor mothers are delayed in establishing a bifidobacteria-dominated microbiota. The delay, the authors said, may be due to difficulties in the infant acquiring a species of bifidobacteria that is geared toward consuming the specific milk sugar delivered by the mother.

The research was conducted using milk samples from 44 mothers in the UC Davis Foods for Health Institute Lactation Study and fecal samples from their infants at four different time points. The researchers determined the secretor status of the mothers: 12 were non-secretor and 32 were secretor mothers. They also measured the amount and type of breast milk sugars and the amount of lactate (a beneficial molecule produced by bifidobacteria) in the infant’s feces.

The researchers determined that more infants fed by secretor mothers had high levels of bifidobacteria — 60 percent of infants versus 37.5 percent at day 6 and 80 percent versus 50 percent at day 120 –- and that infants who had more bifidobacteria had lower amounts of milk sugars left over and higher amounts of lactate in their feces.

One question that remains is whether this pattern holds true in infants living in other places.

“We are beginning to observe that infants from different parts of the world have different patterns of colonization by microbes,” said lead study author Zachary T. Lewis, a postdoctoral fellow.

“The types and levels of bacteria encountered by infants in developing countries is different from the types and levels of bacteria encountered by the babies in our UC Davis cohort, and that might account for some of the differences,” he said.

Maternal secretor status is likely only one of the many factors that influence the infant gut microbiota, Lewis said. The researchers will explore this question further in future studies.

The researchers said that understanding the mechanism behind the observed secretor/non-secretor differences may prove critical to compensating for it in situations where the infants are vulnerable, such as by providing carefully chosen pre- or probiotics. For example, prebiotics and probiotics frequently are given to premature infants  to protect them against NEC, which causes portions of the bowel to necrotize, or die.

“This work significantly advances our efforts to decipher how human milk amazingly orchestrates colonization of the infant gut by helpful bacteria, which then protects and guides intestinal development in the early stages of life. Understanding this incredible sequence of events will provide examples for how to repair this process where it has been disrupted, such as in premature infants or colicky babies,” Mills said.

Other study authors include Jennifer T. Smilowitz, Evan Parker, Danielle G. Lemay and Carlito Lebrilla, all of UC Davis; Sarah M. Totten of UC Davis and Stanford University: Mina Popovic of University of Moedna and Reggio Emilia, Italy; and Maxwell Van Tassel Michael J. Miller and Young-Su Jin of the University of Illinois Urbana-Champagne.

The research was supported by the University of California Discovery Grant Program, the UC Davis Research Investments in the Sciences and Engineering (RISE) Program, the California Dairy Research Foundation, the Bill and Melinda Gates Foundation, National Institutes of Health awards R01HD059127, R01HD065122, 8R01HD061923, R21AT006180, R01AT007079 and the Peter J. Shields Endowed Chair in Dairy Food Science.

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UC Davis leads $4M NIH grant to study skull disorder in infants


International team includes researchers from UC Irvine, UCSF.

Simeon Boyd, UC Davis

By Phyllis Brown, UC Davis

Simeon Boyd, UC Davis professor of genetics and pediatrics, has received a nearly $4 million, five-year grant from the National Institute of Dental and Craniofacial Research to lead a team of physicians and scientists from more than 10 centers in the United States and seven international sites, including Australia, Brazil, Bulgaria, Germany, Hungary, Italy and the United Kingdom, to study craniosynostosis, the premature fusion of the bony plates of the skull in infants.

The researchers are members of the International Craniosynostosis Consortium, whose goal is to identify the genetic and environmental causes of craniosynostosis, which affects approximately 1 in 2,500 newborns worldwide, in order to find clues to prevention, better treatments and, eventually, a cure.

“Our goal is not only to identify the genetic causes of all types of craniosynostosis, but also to facilitate the early detection of the condition, by identifying biomarkers. This may allow for nonsurgical therapeutic intervention in utero in the future,” said Boyd, who is a researcher affiliated with the UC Davis MIND Institute. The conditions also have neurodevelopmental consequences: Approximately 50 percent of patients with craniosynostosis also may have learning disabilities.

During fetal development, the skull is made up of separate bony plates that allow the child’s head to grow after birth. The borders between the plates do not normally fuse completely until a child is about 2, leaving temporary soft spots at the intersections of the seams of the skull.

In craniosynostosis the bones fuse early, causing the child to have an abnormally shaped head. The disorder can lead to complications due to brain compression, such as visual problems and learning disabilities.

“This is not only a skull disease,” Boyd said. “It is a perturbation of the brain and the skull, in which the growing brain is abnormal and causes increased distension of the envelope of the brain so that signaling molecules that normally would keep the sutures open do not function properly.”

Depending upon the severity of the condition, children born with craniosynostosis frequently may require extensive neurosurgical intervention to separate the fused bones of the skull so that the child’s brain can grow.

There are a number of different types of craniosynostosis, depending on which suture is prematurely fused. For example, when the sagittal suture at the top of the head is fused the condition is called in sagittal synostosis, also known as scaphocephaly. Sagittal synostosis is the most common form of the disorder. In coronal synostosis the coronal sutures, which run from the top of the head to the ears, are fused. Several named conditions, such as Muenke syndrome, have craniosynostosis among their symptoms.

In 2012, Boyd and his consortium colleagues published a landmark study in Nature Genetics, which found that two areas of the human genome are associated with a form of the disorder, sagittal craniosynostosis. Although the condition had long been believed to be partially determined by genes – it is three times more common in boys than in girls, and identical twins are much more likely to both be affected than fraternal twins – the genes associated with the disorder had not been previously identified.

Identification of the genetic basis for the conditions is only a first step in preventive and therapeutic strategies, Boyd said.

“We want to prevent babies from being born with these disorders,” he said.

Consortium researchers from the United States include:

  • Jon Bernstein, Stanford University
  •  Michael Cunningham, University of Washington
  •  John Graham, Cedars-Sinai
  •  Virginia Kimonis, UC Irvine
  •  Ophir Klein, UC San Francisco
  •  Pedro Sanchez-Lara, Children’s Hospital Los Angeles
  •  Joan Richtsmeier, Pennsylvania State University
  •  Paul Romitti, University of Iowa
  •  Joan Stoler, Boston Children’s Hospital

International collaborators include:

  •  Andrew Wilkie, Oxford University, United Kingdom
  •  Wanda Lattanzi, Universita Cattolica del Sacro Cuore, Italy
  •  Tony Roscioli, University of Sydney, Australia
  •  Emil Simeonov and Radka Kaneva, Medical University, Sofia Bulgaria
  •  Bernd Wollnik, University of Cologne, Germany
  •  Eva Olah, University of Debrecen, Hungary
  •  Maria Rita Passos-Bueno, University of Sao Paolo, Brazil

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New genetic method promises to advance gene research, control insect pests


In two years, molecular biologists have witnessed a revolution in genome manipulation.

A rare fruit fly in which the left half has been mutated by MCR (hence the pale color) while the right half remains normal. (Photo by Valentino Gantz, UC San Diego)

By Kim McDonald, UC San Diego

Biologists at UC San Diego have developed a new method for generating mutations in both copies of a gene in a single generation that could rapidly accelerate genetic research on diverse species and provide scientists with a powerful new tool to control insect-borne diseases such as malaria as well as animal and plant pests.

Their achievement was published today (March 19) in an advance online paper in the journal Science. It was accomplished by two biologists at UC San Diego working on the fruit fly Drosophila melanogaster who employed a new genomic technology to change how mutations could spread through a population — a concept long established in plants by the father of modern genetics, Gregor Mendel.

“Mendel conducted classic genetic experiments with peas that revealed the fundamental of inheritance in many organisms including humans,” explains Ethan Bier, a professor of biology at UC San Diego whose graduate student, Valentino Gantz, developed the method.  “According to these simple rules of inheritance, the fertilized egg receives one copy of most genes from our mothers and one from our fathers so that the resulting individual has two copies of each gene.”

One advantage of having two copies of a gene is that if one copy carries a non-functional mutation, then the other “good” copy typically can provide sufficient activity to sustain normal function.  Thus, most mutations resulting in loss of gene function are known as recessive, meaning that an organism must inherit two mutant copies of the gene from its parents before an overt defect is observed, as is the case in humans with muscular dystrophy, cystic fibrosis or Tay Sachs disease.

“Because individuals carrying a single mutant copy of a gene often mate with an individual with two normal copies of gene, defects can be hidden for a generation and then show up in the grandchildren,” Bier adds. “This is how genetics has been understood for over a century in diverse organisms including humans, most animals we are familiar with, and many plants.”

But in the past two years, Bier and other molecular biologists have witnessed a veritable revolution in genome manipulation.

“It is now routine to generate virtually any change in the genome of an organism of choice at will,” he notes. “The technology is based on a bacterial anti-viral defense mechanism known as the Cas9/CRISPR system.”

By employing this development in their experiments with laboratory fruit flies, Gantz and Bier demonstrated that by arranging the standard components of this anti-viral defense system in a novel configuration, a mutation generated on one copy of a chromosome in fruit flies spreads automatically to the other chromosome. The end result, Bier says, is that both copies of a gene could be inactivated “in a single shot.”

The two biologists call their new genetic method the “mutagenic chain reaction,” or MCR.

“MCR is remarkably active in all cells of the body with one result being that such mutations are transmitted to offspring via the germline with 95 percent efficiency,” says Gantz, the first author of the paper. “Thus, nearly all gametes of an MCR individual carry the mutation in contrast to a typical mutant carrier in which only half of the reproductive cells are mutant.”

Bier says “there are several profound consequences of MCR. First, the ability to mutate both copies of a gene in a single generation should greatly accelerate genetic research in diverse species. For example, to generate mutations in two genes at once in an organism is typically time consuming, because it requires two generations, and involved, because it requires genetic testing to identify rare progeny carrying both mutations. Now, one should simply be able to cross individuals harboring two different MCR mutants to each other and all their direct progeny should be mutant for both genes.”

“MCR should also be highly effective for dispersing genetic elements in populations to control insect borne diseases such as malaria, dengue and chikungunya as well as animal and plant pests,” he adds. “For example, in the case of malaria, several groups have created genetic cassettes that when introduced into mosquitoes prevent the malarial parasite from propagating thereby blocking infection. A major challenge in the field, however, has been devising a way to disseminate these gene cassettes throughout mosquito populations. MCR offers an obvious solution to this problem since the incorporation of an anti-malarial gene cassette into an MCR element should result in the rapid spread of the gene cassette through the target population. For example, if one in 100 individuals initially carried the cassette, the cassette should spread to virtually all individuals in as few as 10 generations, which is less than one season for mosquitoes.”

It also may be possible to use MCR to spread genes among cells within an individual using modified viruses to carry the genetic elements, Gantz points out. “Since MCR works by targeting specific DNA sequences, in cases where diseased cells have altered DNA as in HIV-infected individuals or some types of cancer, MCR-based methods should be able to distinguish diseased from healthy cells and then be used to selectively either destroy or modify the diseased cells.”

The two biologists note in their paper that while applications of MCR offer potential solutions to important problems in health and human welfare, it could also pose serious potential risks in the wrong hands.

“Could an accidental release of MCR-bearing organisms into the environment result in their spreading potentially deleterious mutation to the vast majority of individuals in a wild population?” says Bier. “We don’t know and would advocate that scientists examine this possibility before permitting experiments using the new method to be used in open laboratories. It is also possible that MCR technology could be intentionally misused, which should be considered as a risk on par with that associated with nefarious uses of select agents.”

Gantz and Bier showed in their experiments, which were conducted in a biosafety laboratory with a high-level of containment to prevent the accidental release of any deleterious mutant genotypes, that propagation of an MCR mutation in flies is remarkably efficient, with a gene conversion rate of about 95 percent.

As a consequence, the two researchers say stringent safety protocols for handling MCR organisms and the prompt establishment of regulatory guidelines for performing experiments with such organisms are imperative. “Development of methods for reversing MCR spread would also provide a means for mitigating risk,” says Gantz.

Bier concurs with others who have raised serious concerns about strategies to disperse genetic elements in pest populations that one other step needs to be taken by scientists. “In an analogy to the famous Asilomar conference concerns held to address concerns raised at the dawn of recombinant DNA technology in the 1970s,” he says, “perhaps a similar meeting should be convened to discuss how MCR technology should be regulated at both federal and institutional levels to assure that it is employed safely to achieve its full potential to ameliorate the human condition.”

The study was funded by two grants (R01 GM067247 and R56 NS029870) from the National Institutes of Health and a generous gift from Sarah Sandell and Michael Marshall. The UC San Diego Technology Transfer Office has applied for a patent to license the new technology.

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New clues about risk of cancer from low-dose radiation


Berkeley Lab research could lead to ways to ID people particularly susceptible to cancer.

By Dan Krotz, Berkeley Lab

Scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) have uncovered new clues about the risk of cancer from low-dose radiation, which in this research they define as equivalent to 100 millisieverts or roughly the dose received from ten full-body CT scans.

They studied mice and found their risk of mammary cancer from low-dose radiation depends a great deal on their genetic makeup. They also learned key details about how genes and the cells immediately surrounding a tumor (also called the tumor microenvironment) affect cancer risk.

In mice that are susceptible to mammary cancer from low-dose radiation, the scientists identified more than a dozen regions in their genomes that contribute to an individual’s sensitivity to low-dose radiation. These genome-environment interactions only become significantly pronounced when the mouse is challenged by low-dose radiation.

The interactions also have a big impact at the cellular level. They change how the tumor microenvironment responds to cancer. Some of these changes can increase the risk of cancer development, the scientists found.

They report their research March 9 in the journal Scientific Reports.

Because mice and humans share many genes, the research could shed light on the effects of low-dose radiation on people. The current model for predicting cancer risk from ionizing radiation holds that risk is directly proportional to dose. But there’s a growing understanding that this linear relationship may not be appropriate at lower doses, since both beneficial and detrimental effects have been reported.

“Our research reinforces this view. We found that cancer susceptibility is related to the complex interplay between exposure to low-dose radiation, an individual mouse’s genes, and their tumor microenvironment,” says Jian-Hua Mao of Berkeley Lab’s Life Sciences Division.

Mao led the research in close collaboration with fellow Life Science Division researchers Gary Karpen, Eleanor Blakely, Mina Bissell and Antoine Snijders, and Mary Helen Barcellos-Hoff of New York University School of Medicine.

The identification of these genetic risk factors could help scientists determine whether some people have a higher cancer risk after exposure to low-dose radiation. It could lead to genetic screening tests that identify people who may be better served by non-radiation therapies and imaging methods.

The scientists used a comprehensive systems biology approach to explore the relationship between genes, low-dose radiation, and cancer. To start, Mao and colleagues developed a genetically diverse mouse population that mimics the diversity of people. They crossed a mouse strain that is highly resistant to cancer with a strain that is highly susceptible. This yielded 350 genetically unique mice. Some were resistant to cancer, some were susceptible, and many were in between.

Next, Mao and colleagues developed a way to study how genes and the tumor microenvironment influence cancer development. They removed epithelial cells from the fourth mammary gland of each mouse, leaving behind the stromal tissue. Half of the mice were then exposed to a single, whole-body, low dose of radiation. They then implanted genetically identical epithelial cells, which were prone to cancer, into the fourth mammary glands that were previously cleared of their epithelial cells.

“We have genetically different mice, but we implanted the same epithelial cells into all of them,” says Mao. “This enabled us to study how genes and the tumor microenvironment — not the tumor itself — affect tumor growth.”

The scientists then tracked each mouse for 18 months. They monitored their tumor development, the function of their immune systems, and the production of cell-signaling proteins called cytokines. The researchers also removed cancerous tissue and examined it under a microscope.

They found that low-dose radiation didn’t change the risk of cancer in most mice. A small minority of mice was actually protected from cancer development by low-dose radiation. And a small minority became more susceptible.

In this latter group, they found thirteen gene-environment interactions, also called “genetic loci,” which contribute to the tumor susceptibility when the mouse is exposed to low-dose radiation. How exactly these genetic loci affect the tumor microenvironment and cancer development is not yet entirely understood.

“In mice that were susceptible to cancer, we found that their genes strongly regulate the contribution of the tumor microenvironment to cancer development following exposure to low-dose radiation,” says Mao.

“If we can identify similar genetic loci in people, and if we could find biomarkers for these gene-environment interactions, then perhaps we could develop a simple blood test that identifies people who are at high risk of cancer from low-dose radiation,” says Mao.

The research was supported by the Department of Energy’s Office of Science.

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New method devised to ID disease markers, step toward personalized medicine


UCLA research holds promise for treating many diseases.

By Stuart Wolpert, UCLA

UCLA life scientists have created an accurate new method to identify genetic markers for many diseases — a significant step toward a new era of personalized medicine, tailored to each person’s DNA and RNA.

The powerful method, called GIREMI (pronounced Gir-REMY), will help scientists to inexpensively identify RNA editing sites, genetic mutations and single nucleotide polymorphisms — tiny variations in a genetic sequence — and can be used to diagnose and predict the risk of a wide range of diseases from cancers to schizophrenia, said Xinshu (Grace) Xiao, senior author of the research and a UCLA associate professor of integrative biology and physiology in the UCLA College.

Details about GIREMI were published March 2 in the advance online edition of the journal Nature Methods. The research was funded by the National Institutes of Health and the National Science Foundation.

Xiao is making the software available on her website as a free download, enabling scientists worldwide to use this potent method in their own research on any number of diseases. President Obama’s budget encourages doctors to design individually tailored treatments based on genetic and molecular differences. This approach, which is called personalized medicine or precision medicine, holds the potential of “delivering the right treatment at the right time, every time, to the right person,” Obama said.

Genes contain RNA editing sites, which are not yet well understood, but appear to hold clues to many diseases. One might think that whatever is in the DNA we inherited from our parents would eventually be expressed in our proteins, but it turns out there is a modification process, called RNA editing, that can contribute to different types of cancer, autism, Alzheimer’s disease, Parkinson’s and many others, Xiao said.

RNA editing modifies nucleotides, whose patterns carry the data required for constructing proteins, which provide the components of cells and tissues — in our genetic material. If you had an “A” nucleotide in your DNA, for example, it may be modified into a “G.”

RNA editing is different from mutations. A mutation is written incorrectly in our genes. In RNA editing, our genetic material is normal, but modifications occur later when a gene is expressed.

GIREMI was researched and designed during the past two years by Xiao and Qing Zhang, a postdoctoral scholar in her laboratory. It is the most accurate and sensitive method for identifying RNA editing sites, as well as SNPs and mutations in RNA. Differentiating SNPs, most of which appear not to be harmful, from RNA editing sites has been very difficult and previously required sequencing a person’s entire genome.

“We can predict RNA editing sites and SNPs without sequencing the whole genome,” said Xiao, a member of UCLA’s Institute for Quantitative and Computational Biosciences, Molecular Biology Institute and also the Jonsson Comprehensive Cancer Center. “Now you don’t have to spend thousands of dollars sequencing the DNA; you can sequence only the RNA. Our method will be easily applicable to all the existing RNA data sets, and will help to identify SNPs and mutations at a large cost reduction from current methods.”

RNA editing is at an early stage. “We are trying to discover as many editing sites as possible,” said Xiao, whose research group is working to apply GIREMI to many diseases. “This method can be easily applied to any RNA sequencing data sets to discover new RNA editing sites that are specific to a certain disease.”

Many RNA editing sites are specific to the brain, Xiao and Zhang found, indicating RNA editing is involved in brain function and neurological disorders. There are more than 10,000 known RNA editing sites in the brain and probably many more, she said.

People have “abundant differences” in RNA editing sites. Studying 93 people whose RNA has been sequenced, Xiao and Zhang found that each person has unique RNA editing sites in their immune system’s lymphoblast cells, which are precursors of white blood cells that protect us from infectious diseases and foreign invaders.

RNA has been widely known as a cellular messenger that makes proteins and carries out DNA’s instructions to other parts of the cell, but is now understood to perform sophisticated chemical reactions and is believed to perform an extraordinary number of other functions, at least some of which are unknown.

Xiao’s research was funded by NIH grants R01HG006264 and U01HG007013, and NSF grant 1262134.

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High school students help grow ‘genetically engineered machine’


UCSF researchers help high school students dive into growing field of synthetic biology.

In addition to their prize-winning science project, the 2014 UCSF iGEM team morphed into superheroes as a creative way to teach synthetic biology to visitors at The Exploratorium.

By Kathleen Masterson, UC San Francisco

Taking molecular parts from living organisms to engineer biological systems sounds a bit like science fiction, but with the help of UCSF researchers, high school students are diving into this growing field of synthetic biology.

It’s all part of a global synthetic biology competition called iGEM.

The international competition aims to engage students in the constantly evolving world of synthetic biology, which is part molecular biology, part systems biology and part genetic engineering. While the “Giant Jamboree” is a fun, lively event, the lab work and presentation preparation are serious work – and real science findings come out of the competition.

This year UCSF’s team won “Best Presentation,” competing against 225 teams hailing from across the globe. Of the two UCSF presenters, one was Eleanor Amidei, who was 17 years old at the time.

To prepare for the competition, the students spend all summer designing their experiments, running them, building a website, developing a presentation and a few other requirements, including submitting a genetic fragment to the synthetic biology bank at MIT.

“At first it was really overwhelming,” said Amidei, who is now a freshmen at UC Berkeley. “It was just scary to be thrown into lab environment. But you kind of just pick up the work as you’re going; you go with it, you read articles, you study more about what you’re doing and it becomes easy, it becomes second nature.”

Bringing high schoolers into the lab

When Wendell Lim, Ph.D., formed the first UCSF team eight years ago, he needed to include participants younger than graduate students to meet the iGEM contest eligibility requirement. Instead of bringing in college students, he partnered with high school teacher George Cachianes who teaches a two-year biotechnology program at Lincoln High School in San Francisco. Every year, a few of the top high school students are invited to join the iGEM team.

This year’s team also partnered with two UC Berkeley undergrads who bring additional programming and graphic design elements to the team skill set.

Lim said the experience benefits both the high school students and the Ph.D. students, who learn to be better mentors.

“What is really unique about this experience is that most of the time, when you do an internship in a lab, you’re assigned to one person who tells you what to do, who gives you instructions,” he said.

But here the group is really a team, said Lim. There’s a lot of brainstorming, and the students, few undergrads, postdocs, all really work together to shape the project. “We’ve defined the sandbox we’ll play in, but exactly what we do and how we do it – they’re a part of defining.”

Real science findings

This year the “sandbox” focused on testing yeast cells to determine if they exhibit collective behavior. That’s a loose term for the “group think” behavior exhibited by seemingly choreographed flocks of birds or tightly synchronized schools of fish swirling in a flash. This kind of group response also occurs in some cells and even electrons – and in tiny yeast cells.

The team discovered that the presence of the group actually influences the behavior of the yeast cells. Though the cells are genetically the same, they respond differently when isolated and respond in synchronized manner when together as a group.

This behavior hadn’t been shown in yeast, said Kara Helmke, the education and outreach coordinator for UCSF’s Center for Systems and Synthetic Biology who works with the iGEM teams.

“The findings were something we didn’t even realize would be possible,” Helmke said. “It was great we could demonstrate it.”

Beyond getting results in the lab, the UCSF team is producing new scientists: Of the more than 60 high school alumni of the program, all are pursuing or have completed science degrees.

“Biotechnology is really a unique aspect of San Francisco and important part of the economy, and it’s exciting to help train the next generation of people,” said Helmke.

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Brain region vulnerable to aging is larger in those with longevity gene variant


1 in 5 carry KLOTHO allele associated with better cognition.

The dorsolateral prefrontal cortex, depicted in blue and red, is larger and linked with better function in those who carry one copy of the KLOTHO gene variant. (Illustration by Michael Griffin Kelly)

By Laura Kurtzman, UC San Francisco

People who carry a variant of a gene that is associated with longevity also have larger volumes in a front part of the brain involved in planning and decision-making, according to researchers at UC San Francisco.

The finding bolsters their previous discovery that middle-aged and older people who carry a single copy of the KLOTHO allele, called KL-VS, performed better on a wide range of cognitive tests. When they modeled KL-VS in mice, they found this strengthened the connections between neurons and enhanced learning and memory.

KLOTHO codes for a protein, called klotho, which is produced in the kidney and brain and regulates many different processes in the body. About 1 in 5 people carry a single copy of KL-VS, which increases klotho levels and is associated with a longer lifespan and better heart and kidney function. A small minority, about 3 percent, carries two copies, which is associated with a shorter lifespan.

Examining part of prefrontal cortex

In the current study, published today (Jan. 27), in Annals of Clinical and Translational Neurology, researchers scanned the brains of 422 cognitively normal men and women aged 53 and older to see if the size of any brain area correlated with carrying one, two or no copies of the allele.

They found that the KLOTHO gene variant predicted the size of a region called the right dorsolateral prefrontal cortex (rDLPFC), which is especially vulnerable to atrophy as people age. Deterioration in this area may be one reason why older people have difficulty suppressing distracting information and doing more than one thing at a time.

Researchers found that the rDLPFC shrank with age in all three groups, but those with one copy of KL-VS – about a quarter of the study group – had larger volumes than either non-carriers or those with two copies. Researchers also found that the size of the rDLPFC predicted how well the three groups performed on cognitive tests, such as working memory – the ability to keep a small amount of newly acquired information in mind – and processing speed. Both tests are considered to be good measures of the planning and decision-making functions that the rDLPFC controls.

“We’ve known for a long time that people lose cognitive abilities as they age, but now we’re beginning to understand that factors like klotho can give people a boost and confer resilience in aging,” said senior author Dena Dubal, M.D., Ph.D., assistant professor of neurology at UCSF and the David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease. “Genetic variation in KLOTHO could help us predict brain health and find ways to protect people from the devastating diseases that happen to us as we grow old, like Alzheimer’s and other dementias.”

Bigger size means better function

In statistical tests, the researchers concluded that the larger rDLPFC volumes seen in single copy KL-VS carriers accounted for just 12 percent of the overall effect that the variant had on the abilities tested.

However, the allele may have other effects on the brain, such as increasing levels or changing the actions of the klotho protein to enhance synaptic plasticity, or the connections between neurons. In a previous experiment, they found that raising klotho in mice increased the action of a cell receptor critical to forming memories.

“The brain region enhanced by genetic variation in KLOTHO is vulnerable in aging and several psychiatric and neurologic diseases including schizophrenia, depression, substance abuse and frontotemporal dementia,” said Jennifer Yokoyama, Ph.D., first author and assistant professor of neurology at UCSF. “In this case, bigger size means better function. It will be important to determine whether the structural boost associated with carrying one copy of KL-VS can offset the cognitive deficits caused by disease.”

Other authors of the study include Virginia Sturm, Luke Bonham, Joel Kramer and Bruce Miller of UCSF; Eric Klein and Giovanni Coppola of UCLA; Lei Yu and David Bennett of Rush University Medical Center; and Konstantinos Arfanakis of Rush and the Illinois Institute of Technology.

The study was funded by the Larry L. Hillblom Foundation, the National Institute on Aging, the American Federation for Aging Research, the Coulter-Weeks Foundation and the Bakar Foundation.

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Study pinpoints two genes that increase risk for PTSD


Heredity may influence people’s predisposition for post-traumatic stress disorder.

Armen Goenjian, UCLA

By Elaine Schmidt, UCLA

Why do some people develop post-traumatic stress disorder while others who suffered the same ordeal do not? A new UCLA discovery may shed light on the answer.

UCLA scientists have linked two genes to the debilitating mental disorder, suggesting that heredity influences a person’s risk of developing PTSD. Published in the February 2015 edition of the Journal of Affective Disorders, the findings could provide a biological basis for diagnosing and treating PTSD more effectively in the future.

“Many people suffer with post-traumatic stress disorder after surviving a life-threatening ordeal like war, rape or a natural disaster,” explained lead author Dr. Armen Goenjian, a researcher at the Semel Institute for Neuroscience and Human Behavior at UCLA. “But not everyone who experiences trauma suffers from PTSD. We investigated whether PTSD has genetic underpinnings that make some people more vulnerable to the syndrome than others.”

In 1988, Goenjian, an Armenian American, rushed to Spitak, Armenia, after a 6.8 magnitude earthquake devastated the country. The temblor leveled entire towns and cities, killing more than 25,000 people, two-thirds of them children.

With support from the Armenian Relief Society, Goenjian and his colleagues helped establish a pair of psychiatric clinics that treated earthquake survivors for 21 years. A dozen multigenerational families in northern Armenia agreed to allow their blood samples to be sent to UCLA, where Goenjian and his colleagues combed the DNA of 200 individuals for genetic clues to psychiatric vulnerability.

In 2012, his team discovered that PTSD was more common in survivors who carried two gene variants associated with depression. In the current study, Goenjian and first author Julia Bailey, an adjunct assistant professor of epidemiology at the UCLA Fielding School of Public Health, focused on two genes, COMT and TPH-2, which play important roles in brain function.

COMT is an enzyme that degrades dopamine, a neurotransmitter that controls the brain’s reward and pleasure centers and helps regulate mood, thinking, attention and behavior. Too much or too little dopamine can influence various neurological and psychological disorders.

TPH-2 controls the production of serotonin, a neurotransmitter that regulates mood, sleep and alertness — all of which are disrupted in PTSD. Serotonin is the target of a group of drugs called selective serotonin reuptake inhibitors, or SSRIs, which were designed to treat depression. Now, more physicians are prescribing SSRIs to treat disorders beyond depression, including PTSD.

“We found a significant association between variants of COMT and TPH-2 with PTSD symptoms, suggesting that these genes contribute to the onset and persistence of the disorder,” Goenjian said. “Our results indicate that people who carry these genetic variants may be at higher risk of developing PTSD.”

The team used the most recent PTSD criteria from the American Psychiatric Association’s diagnostic manual to measure genes’ role in predisposing someone to the disorder. The new criteria increased estimates of the degree to which PTSD is genetic to 60 percent; estimates based on older criteria reached only 41 percent.

“Assessments of patients based upon the latest diagnostic criteria may boost the field’s chances of finding new genetic markers for PTSD,” Goenjian said. “We hope our findings will lead to molecular methods for screening people at risk for this disorder and identify new drug therapies for prevention and treatment.”

Goenjian cautioned that PTSD is likely caused by multiple genes, and that more research must be done to find more of the genes involved.

PTSD affects about 7 percent of Americans. It has been a pressing health issue for many veterans returning from tours in Iraq and Afghanistan.

The study’s co-authors were Ernest Noble and Sugandha Dandekar, both of UCLA; Alan Steinberg of the UCLA–Duke National Childhood Center for Traumatic Stress; David Walling of the Collaborative Neuroscience Network; and Sofia Stepanian of UC Riverside.

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Iron overload disease causes rapid growth of potentially deadly bacteria


Deficiency of the hormone hepcidin makes people vulnerable to Vibrio vulnificus.

By Amy Albin, UCLA

Every summer, the news reports on a bacterium called Vibrio vulnificusfound in warm saltwater that causes people to get sick, or die, after they eat raw tainted shellfish or when an open wound comes in contact with seawater.

People with a weakened immune system, chronic liver disease or iron overload disease are most at risk for severe illness. Vibrio vulnificus infections in high-risk individuals are fatal 50 percent of the time.

Now, researchers at UCLA have figured out why those with iron overload disease are so vulnerable. People with the common genetic iron overload disease called hereditary hemochromatosis have a deficiency of the iron-regulating hormone hepcidin and thus develop excess iron in their blood and tissue, providing prime growth conditions for Vibrio vulnificus.

The study also found that minihepcidin, a medicinal form of the hormone hepcidin that lowers iron levels in blood, could cure the infection by restricting bacterial growth.

The early findings were reported online today (Jan. 14) in the journal Cell Host and Microbe.

“This is the first time that the association of hepcidin deficiency and susceptibility to Vibrio vulnificus infection was tested,” said senior author Dr. Yonca Bulut, a clinical professor of pediatrics at Mattel Children’s Hospital at UCLA and a researcher with the UCLA Children’s Discovery and Innovation Institute. “The dramatic effectiveness of the new treatment, even after the infection was established, was impressive.”

To conduct the study, researchers compared the fatality of Vibrio vulnificus infection in healthy mice with mice that lacked hepcidin, modeling human hereditary hemochromatosis. The results showed that the infection was much more lethal in hepcidin-deficient mice because they could not decrease iron levels in the blood in response to infection, a process mediated by hepcidin in healthy mice.

Giving minihepcidin to susceptible hepcidin-deficient mice to lower the amount of iron in the blood prevented infection if the hormone was given before the Vibrio vulnificus was introduced. Additionally, mice given minihepcidin three hours after the bacterium was introduced were cured of any infection.

Hereditary hemochromatosis is a genetic disease that causes the body to absorb and store too much iron. It affects as many as 1 in every 200 people in the United States. Since it can take decades for the body to store damaging levels of iron, many people may not be aware that they have the disease until signs of the condition begin to appear later in life.

The co-directors of the UCLA Center for Iron Disorders, Dr. Tomas Ganz, a professor of medicine and pathology at the David Geffen School of Medicine at UCLA, and Elizabeta Nemeth, a professor of medicine at UCLA, led the invention of minihepcidins at UCLA. Minihepcidins are being developed for treatment of iron-overload disorders, such as hereditary hemochromatosis and Cooley’s anemia. The use of minihepcidin to treat potentially lethal infections is a possible new application.

“We found that hepcidin is required for resistance to a Vibrio vulnificus infection,” said the study’s lead author Joao Arezes, a visiting graduate student from the University of Porto in Portugal. “The development of the treatment tested in mouse models could reduce the high mortality rate of this disease.”

The next stage of research is to understand why Vibrio vulnificus bacteria become so lethal when iron levels are high, and to learn which other microbes respond similarly to excess iron.

The research was conducted at the UCLA Center for Iron Disorders.

Other study authors were Grace Jung, Victoria Gabayan, Erika Valore, Piotr Ruchala, Ganz and Nemeth, all of UCLA, and Paul Gulig of the University of Florida.

The study was funded by the UCLA Today’s and Tomorrow’s Children Fund, the UCLA Stein/Oppenheimer Endowment Award, the UCLA Children’s Discovery and Innovation Institute and the National Institutes of Health (grant R01 DK090554).

The Regents of the University of California is the owner of patents and patent applications directed at minihepcidins and methods of use thereof, which are managed by UCLA’s Office of Intellectual Property and Industry Sponsored Research. This intellectual property is licensed to Merganser Biotech, for which authors Ruchala, Ganz and Nemeth are scientific advisors and equity holders. Other disclosures are available in the manuscript.

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New therapy holds promise for restoring vision


It has several advantages over other sight restoration therapies now under investigation.

Benjamin Gaub and John Flannery observing a mouse in a water maze, in which the mouse swims to a platform designated by bright flashing lights. (Photo by Mervi Kuronen)

By Robert Sanders, UC Berkeley

A new genetic therapy not only helped blind mice regain enough light sensitivity to distinguish flashing from non-flashing lights, but also restored light response to the retinas of dogs, setting the stage for future clinical trials of the therapy in humans.

The therapy employs a virus to insert a gene for a common ion channel into normally blind cells of the retina that survive after the light-responsive rod and cone photoreceptor cells die as a result of diseases such as retinitis pigmentosa. Photoswitches – chemicals that change shape when hit with light – are then attached to the ion channels to make them open in response to light, activating the retinal cells and restoring light sensitivity.

Afflicting people of all ages, retinitis pigmentosa causes a gradual loss of vision, akin to losing pixels in a digital camera. Sight is lost from the periphery to the center, usually leaving people with the inability to navigate their surroundings. Some 100,000 Americans suffer from this group of inherited retinal diseases.

In a paper appearing online this week in the early edition of the journal Proceedings of the National Academy of Sciences, University of California, Berkeley, scientists who invented the photoswitch therapy and vision researchers at the School of Veterinary Medicine of the University of Pennsylvania (PennVet) report that blind mice regained the ability to navigate a water maze as well as normal mice.

The treatment worked equally well to restore light responses to the degenerated retinas of mice and dogs, indicating that it may be feasible to restore some light sensitivity in blind humans.

“The dog has a retina very similar to ours, much more so than mice, so when you want to bring a visual therapy to the clinic, you want to first show that it works in a large animal model of the disease,” said lead researcher Ehud Isacoff, professor of molecular and cell biology at UC Berkeley. “We’ve now showed that we can deliver the photoswitch and restore light response to the blind retina in the dog as well as in the mouse, and that the treatment has the same sensitivity and speed of response. We can reanimate the dog retina.”

The therapy has several advantages over other sight restoration therapies now under investigation, says vision scientist John Flannery, UC Berkeley professor of vision science and of molecular and cell biology. It uses a virus already approved by the Food and Drug Administration for other genetic therapies in the eye; it delivers an ion channel gene similar to one normally found in humans, unlike others that employ genes from other species; and it can easily be reversed or adjusted by supplying new chemical photoswitches. Dogs with the retinal degeneration provide a key test of the new therapy.

“Our ability to test vision is very, very limited in mice because, even in the healthy state, they are not very visual animals, their behaviors are largely driven by their other senses,” he says. “Dogs have a very sophisticated visual system, and are being used already for testing ophthalmic gene therapy.”

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How stem cells can be activated to help immune system fight infection


UCLA scientists show crucial role of genes Scalloped and Yorkie.

UCLA researchers have discovered that the Scalloped (above) and Yorkie genes play a key role in how progenitor stem cells are activated to fight infection. (Image by Dr. Julian Martinez-Agosto Lab, UCLA)

By Peter Bracke, UCLA

In a study led by Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research member Dr. Julian Martinez-Agosto, UCLA scientists have shown that two genes not previously known to be involved with the immune system play a crucial role in how progenitor stem cells are activated to fight infection.

This discovery lays the groundwork for a better understanding of the role progenitor cells can play in immune system response and could lead to the development of more effective therapies for a wide range of diseases.

The two-year study was published in the current issue of the journal Current Biology.

Progenitor cells are the link between stem cells and fully differentiated cells of the blood system, tissues and organs. This maturation process, known as differentiation, is determined in part by the original environment that the progenitor cell came from, called the niche. Many of these progenitors are maintained in a quiescent state or “standby mode” and are ready to differentiate in response to immune challenges such as stress, infection or disease.

Dr. Gabriel Ferguson, a postdoctoral fellow in Martinez-Agosto’s lab and first author of the study, built upon the lab’s previous research that utilized the blood system of the fruit fly species Drosophila to show that a specific set of signals must be received by progenitor cells to activate their differentiation into cells that can work to fight infection after injury. Ferguson focused on two genes previously identified in stem cells but not in the blood system, named Yorkie and Scalloped, and discovered that they are required in a newly characterized cell type called a lineage specifying cell. These cells then essentially work as a switch, sending the required signal to progenitor cells.

The researchers further discovered that when the progenitor cells did not receive the required signal, the fly would not make the mature cells required to fight infection. This indicates that the ability of the blood system to fight outside infection and other pathogens is directly related to the signals sent by this new cell type.

“The beauty of this study is that we now have a system in which we can investigate how a signaling cell uses these two genes, Yorkie and Scalloped, which have never before been shown in blood, to direct specific cells to be made,” said Martinez-Agosto, associate professor of human genetics. “It can help us to eventually answer the question of how our body knows how to make specific cell types that can fight infection.”

The researchers said that they hope future studies will examine these genes beyond Drosophila and extend to mammalian models, and that the system will be used by the research community to study the role of the genes Yorkie and Scalloped in different niche environments.

“At a biochemical level, there is a lot of commonality between the molecular machinery in Drosophila and that in mice and humans,” Ferguson said. “This study can further our shared understanding of how the microenvironment can regulate the differentiation and fate of a progenitor or stem cell.”

Martinez-Agosto noted, “Looking at the functionality of these genes and their effect on the immune response has great potential for accelerating the development of new targeted therapies.”

Ferguson’s research on this project was supported by a Cellular and Molecular Biology National Institutes of Health predoctoral training grant. Additional funding was provided by the David Geffen School of Medicine at UCLA.

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Statins reverse learning disabilities caused by Noonan syndrome


UCLA mouse study shows drugs overcome mutation, even in adult brain.

Alcino Silva, UCLA

UCLA scientists have discovered that statins, a popular class of cholesterol drugs, reverse the learning disabilities caused by a genetic disorder called Noonan syndrome.

Their findings were published online Nov. 10 by the journal Nature Neuroscience.

The disorder, which is caused by a genetic mutation, can disrupt a child’s development in many ways. It often causes unusual facial features, short stature, heart defects and developmental delays, including learning disabilities. No treatment is currently available.

“Noonan syndrome affects 1 in 2,000 people, and up to half of these patients struggle with learning disabilities,” said Alcino Silva, the study’s principal investigator and a professor of neurobiology, psychiatry and psychology at the David Geffen School of Medicine at UCLA. “Our approach identified the mechanism causing the disease, as well as a treatment that reversed its effects in adult mice. We are excited about these findings because they suggest that the treatment we developed may help the millions of Noonan patients with intellectual disabilities.”

While many genes contribute to Noonan syndrome, there is one gene that causes about half of all cases. This gene encodes for a protein that regulates another protein called Ras, which controls how brain cells talk to each other, enabling learning to take place.

Working with first author Young-Seok Lee, Silva studied mice that were genetically engineered to develop Noonan syndrome. They discovered that the predominant mutation that leads to Noonan creates hyperactive Ras, which disrupts cellular conversations and undermines the learning process.

“The act of learning creates physical changes in the brain, much like grooves on a record,” said Silva, who also is a member of the UCLA Brain Research Institute and UCLA Integrative Center for Learning and Memory. “Surplus Ras tips the balance between switching signals on and off in the brain. This interrupts the delicate cell communication needed by the brain to record learned information.”

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