TAG: "Genetics"

Study discovers therapy to correct a severe chromosome defect


Induced pluripotent stem cell reprogramming offers potential to correct abnormal chromosomes.

Anthony Wynshaw-Boris

Anthony Wynshaw-Boris

Geneticists from Ohio, California and Japan joined forces in a quest to correct a faulty chromosome through cellular reprogramming. Their study, published online Jan. 12 in Nature, used stem cells to correct a defective “ring chromosome” with a normal chromosome. Such therapy has the promise to correct chromosome abnormalities that give rise to birth defects, mental disabilities and growth limitations.

“In the future, it may be possible to use this approach to take cells from a patient that has a defective chromosome with multiple missing or duplicated genes and rescue those cells by removing the defective chromosome and replacing it with a normal chromosome,” said senior author Anthony Wynshaw-Boris, M.D., Ph.D., James H. Jewell M.D. ’34 Professor of Genetics and chair of Case Western Reserve School of Medicine Department of Genetics and Genome Sciences and University Hospitals Case Medical Center.

Wynshaw-Boris led this research while a professor in pediatrics, the Institute for Human Genetics and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UC San Francisco before joining the faculty at Case Western Reserve in June 2013.

Individuals with ring chromosomes may display a variety of birth defects, but nearly all persons with ring chromosomes at least display short stature due to problems with cell division. A normal chromosome is linear, with its ends protected, but with ring chromosomes, the two ends of the chromosome fuse together, forming a circle. This fusion can be associated with large terminal deletions, a process where portions of the chromosome or DNA sequences are missing. These deletions can result in disabling genetic disorders if the genes in the deletion are necessary for normal cellular functions.

The prospect for effective countermeasures has evaded scientists — until now. The international research team discovered the potential for substituting the malfunctioning ring chromosome with an appropriately functioning one during reprogramming of patient cells into induced pluripotent stem cells (iPSCs). iPSC reprogramming is a technique that was developed by Shinya Yamanaka, M.D., Ph.D., a co-corresponding author on the Nature paper. Yamanaka is a senior investigator at the UCSF-affiliated Gladstone Institutes, a professor of anatomy at UCSF, and the director of the Center for iPS Cell Research and Application (CiRA) at the Institute for Integrated Cell-Material Sciences (iCeMS) in Kyoto University. He won the Nobel Prize in Medicine in 2012 for developing the reprogramming technique.

Marina Bershteyn, Ph.D., a postdoctoral fellow in the Wynshaw-Boris lab at UCSF, along with Yohei Hayashi, Ph.D., a postdoctoral fellow in the Yamanaka lab at the Gladstone Institutes, reprogrammed skin cells from three patients with abnormal brain development due to a rare disorder called Miller-Dieker Syndrome, which results from large terminal deletions in one arm of chromosome 17. One patient had a ring chromosome 17 with the deletion, and the other two patients had large terminal deletions in one copy of chromosome 17, but not a ring. Additionally, each of these patients had one normal chromosome 17.

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Berkeley discoveries named top 2013 breakthroughs


Cancer immunotherapy earns Science magazine’s top spot.

James Allison in 1993, when he was conducting research at UC Berkeley on a promising immunotherapy now reaching fruition. (Photo by Jane Scherr)

James Allison in 1993, when he was conducting research at UC Berkeley on a promising immunotherapy now reaching fruition.

Science magazine’s Breakthrough of the Year for 2013 – cancer immunotherapy – emerged from work conducted at UC Berkeley in the 1990s, while a 2012 UC Berkeley discovery was named one of nine runners up for the annual honor.

The Breakthrough of the Year and runners up were announced in the Dec. 20 issue of the journal, the main publication of the American Association for the Advancement of Science.

Cancer immunotherapy earned its top spot, according to a Science article by Jennifer Couzin-Frankel, “because this year, clinical trials have cemented its potential in patients and swayed even the skeptics. The field hums with stories of lives extended: the woman with a grapefruit-size tumor in her lung from melanoma, alive and healthy 13 years later; the 6-year-old near death from leukemia, now in third grade and in remission; the man with metastatic kidney cancer whose disease continued fading away even after treatment stopped.”

Among the runners up was a gene-editing technique called CRISPR that “touched off an explosion of research in 2013,” Science wrote. The technique, discovered in 2012 by Jennifer Doudna and Martin Jinek of the Howard Hughes Medical Institute at UC Berkeley and Emmanuelle Charpentier of the Laboratory for Molecular Infection Medicine-Sweden, allows very precise manipulation of genes and may make gene therapy a realistic alternative for patients with genetic diseases.

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Study sheds light on muscle-to-bone transformation


Stem cells used to model disease that causes abnormal bone growth.

Edward Hsiao, UC San Francisco

Edward Hsiao, UC San Francisco

Researchers have developed a new way to study bone disorders and bone growth, using stem cells from patients afflicted with a rare, genetic bone disease. The approach, based on Nobel-Prize winning techniques, could illuminate the illness, in which muscles and tendons progressively turn into bone, and addresses the similar destructive process that afflicts a growing number of veterans who have suffered blast injuries — including traumatic amputations or injuries to the brain and nervous system. This insidious hardening of tissues also grips some patients following joint replacement or severe bone injuries.

The disease model, described in a new study by a UC San Francisco-led team, involves taking skin cells from patients with the bone disease, reprogramming them in a lab dish to their embryonic state, and deriving stem cells from them.

Once the team derived the stem cells, they identified a cellular mechanism that drives abnormal bone growth in the thus-far untreatable bone disease, called fibrodysplasiaossificans progressiva (FOP). Furthermore, they found that certain chemicals could slow abnormal bone growth in the stem cells, a discovery that might help guide future drug development.

Clinically, the genetic and trauma-caused conditions are very similar, with bone formation in muscle leading to pain and restricted movement, according to the leader of the new study, Edward Hsiao, M.D., Ph.D., an endocrinologist who cares for patients with rare and unusual bone diseases at the UCSF Metabolic Bone Clinic in the Division of Endocrinology and Metabolism.

The human cell-based disease model is expected to lead to a better understanding of these disorders and other illnesses, Hsiao said.

“The new FOP model already has shed light on the disease process in FOP by showing that the mutated gene can affect different steps of bone formation,” Hsiao said. “These different stages represent potential targets for limiting or stopping the progression of the disease, and may also be useful for blocking abnormal bone formation in other conditions besides FOP. The human stem-cell lines we developed will be useful for identifying drugs that target the bone-formation process in humans.”

The team’s development of, and experimentation with, the human stem-cell disease model for FOP, published in the December issue of the Orphanet Journal of Rare Diseases, is a realization of the promise of research using stem cells of the type known as induced pluripotent stem (iPS) cells, immortal cells of nearly limitless potential, derived not from embryos, but from adult tissues.

Shinya Yamanaka, M.D., Ph.D., a UCSF professor of anatomy and a senior investigator with the UCSF-affiliated Gladstone Institutes, as well as the director of the Center for iPSCell Research and Application (CiRA) and a principal investigator at Kyoto University, shared the Nobel Prize in 2012 for discovering how to make iPS cells from skin cells using a handful of protein “factors.” These factors guide a reprogramming process that reverts the cells to an embryonic state, in which they have the potential to become virtually any type of cell.

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Protein interaction may drive most common genetic cause of Parkinson’s


Findings challenge conventional wisdom, point to new therapeutic strategies.

Steve Finkbeiner and Gaia Skibinski

Steve Finkbeiner and Gaia Skibinski

The most devastating aspect of Parkinson’s disease may not be its debilitating symptoms, which rob its victims of their ability to control their own movement. It may not be the millions around the world and their families who suffer each day from the disease’s harmful effects. Instead, it may in fact be that its root causes remain largely a mystery. But now, scientists at the Gladstone Institutes have discovered how the interplay between two proteins in the brain fuels the degradation and death of the class of brain cells, or neurons, that leads to Parkinson’s. These findings, which stand in stark contrast to conventional wisdom, lay much-needed groundwork for developing treatments that target the disease’s elusive underlying mechanisms.

In the latest issue of the Journal of Neuroscience, researchers in the laboratory of Gladstone Investigator Steve Finkbeiner, M.D., Ph.D., harnessed the power of their one-of-a-kind robotic microscope to track the lifespan of individual neurons over time. The microscope has been used to study a variety of neurodegenerative diseases, and in this study, they focus their attention on LRRK2 — the most common genetic cause of Parkinson’s.

Scientists have long known that mutations in LRRK2 cause misfolded versions of the LRRK2 protein to accumulate in neurons. The prevailing hypothesis has been that misfolded LRRK2 boosts the activity of a type of enzyme called kinase, and that this heightened kinase activity is what drives cell death. Scientists have also looked to the fact that mutant LRRK2 tends to clump together into so-called inclusion bodies (IBs) as another contributor to the disease’s progression.

“As a result, researchers have used the presence of IBs and heightened kinase activity as a proxy for measuring LRRK2’s harmful effects, rather than measuring LRRK2 levels directly,” explained Finkbeiner, who is the associate director of neurological research at Gladstone as well as a professor at the University of California, San Francisco, with which Gladstone is affiliated. “But we were unconvinced that these were the main drivers of cell death — so we decided to take a closer look at what was happening inside the cell.”

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Nutrition influences metabolism through circadian rhythms


Reprogramming of liver “clock” may contribute to metabolic disorders, UC Irvine study finds.

Paolo Sassone-Corsi, UC Irvine

Paolo Sassone-Corsi, UC Irvine

A high-fat diet affects the molecular mechanism controlling the internal body clock that regulates metabolic functions in the liver, UC Irvine scientists have found. Disruption of these circadian rhythms may contribute to metabolic distress ailments, such as diabetes, obesity and high blood pressure.

There’s good news, though. The researchers also discovered that returning to a balanced, low-fat diet normalized the rhythms. This study reveals that the circadian clock is able to reprogram itself depending on a diet’s nutritional content – which could lead to the identification of novel pharmacological targets for controlled diets.

UC Irvine’s Paolo Sassone-Corsi, the Donald Bren Professor of Biological Chemistry and one of the world’s leading researchers on the genetics of circadian rhythms, led the study, which appears in Cell.

Circadian rhythms of 24 hours govern fundamental physiological functions in virtually all organisms. The circadian clocks are intrinsic time-tracking systems in our bodies that anticipate environmental changes and adapt themselves to the appropriate time of day. Changes to these rhythms can profoundly influence human health. Up to 15 percent of people’s genes are regulated by the day-night pattern of circadian rhythms, including those involved with metabolic pathways in the liver.

A high-fat diet reprograms the liver clock through two main mechanisms. One blocks normal cycles by impeding the clock regulator genes called CLOCK:BMAL1. The other initiates a new program of oscillations by activating genes that normally do not oscillate, principally through a factor called PPAR-gamma. Previously implicated in inflammatory responses and the formation of fatty tissue, this factor oscillates with a high-fat diet.

It’s noteworthy, Sassone-Corsi said, that this reprogramming takes place independent of the state of obesity; rather, it’s solely dependent upon caloric intake – showing the remarkable adaptability of the circadian clock.

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How cells remodel after ultraviolet radiation


UC San Diego esearchers map cell’s genetic interactions to fix damaged DNA.

Trey Ideker, UC San Diego

Trey Ideker, UC San Diego

Researchers at the UC San Diego School of Medicine, with colleagues in The Netherlands and United Kingdom, have produced the first map detailing the network of genetic interactions underlying the cellular response to ultraviolet (UV) radiation.

The researchers say their study establishes a new method and resource for exploring in greater detail how cells are damaged by UV radiation and how they repair themselves. UV damage is one route to malignancy, especially in skin cancer, and understanding the underlying repair pathways will better help scientists to understand what goes wrong in such cancers.

The findings will be published in the Dec. 26 issue of Cell Reports.

Principal investigator Trey Ideker, Ph.D., division chief of genetics in the UC San Diego School of Medicine and a professor in the UC San Diego departments of medicine and bioengineering, and colleagues mapped 89 UV-induced functional interactions among 62 protein complexes. The interactions were culled from a larger measurement of more than 45,000 double mutants, the deletion of two separate genes, before and after different doses of UV radiation.

Specifically, they identified interactive links to the cell’s chromatin structure remodeling (RSC) complex, a grouping of protein subunits that remodel chromatin – the combination of DNA and proteins that make up a cell’s nucleus – during cell mitosis or division. “We show that RSC is recruited to places on genes or DNA sequences where UV damage has occurred and that it helps facilitate efficient repair by promoting nucleosome remodeling,” said Ideker.

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Recurrent brain cancers follow distinctive genetic paths


Commonly used brain tumor chemotherapy drug may propel recurrent tumors to malignancy.

Joseph Costello, UC San Francisco

Joseph Costello, UC San Francisco

Brain tumors known as low-grade gliomas can be treated with surgery, sometimes in combination with chemotherapy and/or radiation therapy, with some patients living for decades after treatment. But because these tumors infiltrate normal brain tissue, it is difficult to remove them completely, and more often than not, gliomas recur at the same site in the brain, in some cases many years after surgery.

Now, a team led by scientists from UC San Francisco has discovered that recurrent gliomas may have genetic profiles that are markedly different from those of the initial tumors that spawned them, and has shown that these differences are vastly amplified when a commonly used chemotherapy drug is employed to treat the initial tumors.

The new work, published online in Science Express on Dec. 12, may prompt a rethinking of targeted approaches to glioma treatment based on genetic profiling of tumors, and also argues for the judicious use of temozolomide (TMZ), the chemotherapy agent most often used in glioma cases, the team said. The findings on TMZ have prompted the launch of a clinical trial, expected to open at UCSF in early 2014, which will explore the use of a targeted drug to block TMZ’s deleterious effects.

In developing a plan for cancer therapy, the genetic characteristics of a patient’s tumor are increasingly used to customize treatment, but “if the tumor recurrence has a genetic pattern that differs in some way from the initial tumor, using only the initial tumor as a guide might be missing the mark,” said Joseph F. Costello, Ph.D., professor and Karen Osney Brownstein Endowed Chair of neurological surgery and co-senior author of the new research with Barry S. Taylor, Ph.D., assistant professor of epidemiology and biostatistics.

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Molecular sensor detects early signs of MS


Innovative approach in animal models could one day serve as early indicator of disease.

Katerina Akassoglou

Katerina Akassoglou

For some, the disease multiple sclerosis (MS) attacks its victims slowly and progressively over a period of many years. For others, it strikes without warning in fits and starts.

But all patients share one thing in common: the disease had long been present in their nervous systems, under the radar of even the most sophisticated detection methods. But now, scientists at the UC San Francisco-affiliated Gladstone Institutes have devised a new molecular sensor that can detect MS at its earliest stages — even before the onset of physical signs.

In a new study from the laboratory of Gladstone investigator Katerina Akassoglou, Ph.D., scientists reveal in animal models that the heightened activity of a protein called thrombin in the brain could serve as an early indicator of MS.

By developing a fluorescently labeled probe specifically designed to track thrombin, the team found that active thrombin could be detected at the earliest phases of MS — and that this active thrombin correlates with disease severity. These findings, reported online in Annals of Neurology, shed light on some of MS’ most elusive mechanisms and could spur the development of a much-needed early-detection method for this devastating disease.

MS, which afflicts millions of people worldwide, develops when the body’s immune system attacks the protective myelin sheath that surrounds nerve cells. This attack damages the nerve cells, leading to a host of symptoms that include numbness, fatigue, difficulty walking, paralysis and loss of vision. While some drugs can delay these symptoms, they do not treat the disease’s underlying causes — causes that researchers are only just beginning to understand.

Last year, Akassoglou, a professor in residence in the UCSF School of Medicine, and her team found that a key step in the progression of MS is the disruption of the blood brain barrier (BBB). This barrier physically separates the brain from the blood circulation and if it breaks down, a blood protein called fibrinogen seeps into the brain. When this happens, thrombin responds by converting fibrinogen into fibrin — a protein that should normally not be present in the brain. As fibrin builds up in the brain, it triggers an immune response that leads to the degradation of the nerve cells’ myelin sheath, over time contributing to the progression of MS.

“We already knew that the buildup of fibrin appears early in the development of MS — both in animal models and in human patients, so we wondered whether thrombin activity could in turn serve as an early marker of disease.” said Akassoglou, who directs the Gladstone Center for In Vivo Imaging Research (CIVIR). “In fact, we were able to detect thrombin activity even in our animal models even before they exhibited any of the disease’s neurological signs.”

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Origin of Alzheimer’s gene discovered


UC Santa Barbara researcher tracks source to a single founder dating from Habsburg Spain.

Kenneth Kosik, UC Santa Barbara

Kenneth Kosik, UC Santa Barbara

The age and origin of the E280A gene mutation responsible for early-onset Alzheimer’s in a Colombian family with an unusually high incidence of the disease has been traced to a single founder dating from the 16th century.

Kenneth S. Kosik, Harriman Professor in Neuroscience at UC Santa Barbara and co-director of the campus’s Neuroscience Research Institute (NRI), conducted the study. The findings appear in the journal Alzheimer’s & Dementia.

“Some mutations just increase your risk, but this mutation is not a risk,” Kosik said. “This mutation is highly penetrant, which means that if you carry the mutation, you will get early-onset Alzheimer’s disease.”

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Brave new world


UCSF pharmacy school one of nation’s first to offer students genetic testing for drug response.

Brave new world illustrationWhen Julia Choi’s grandmother suffered her third stroke, a doctor in the emergency room gave her blood thinner medication to prevent another stroke. Not long after, Choi’s grandmother experienced gastrointestinal bleeding – a common side effect of blood thinners. She later passed away. Choi never found out if the bleeding was indeed caused by the drug or by something else.

The memories of her grandmother’s struggle came flooding back to Choi last spring when she took a course in genetics and drug response as a first-year pharmacy student at UC San Francisco. Not only did she learn that some people carry variants in their genes that cause adverse reactions to clopidogrel, the drug her grandmother had been given, but Choi also had the opportunity to have her own genes tested for such mutations.

The UCSF School of Pharmacy is one of the first pharmacy schools in the nation to offer its students genetic testing for drug response. It’s just one way UCSF is educating students about precision medicine – an emerging approach that collects and integrates vast amounts of data and new technologies to develop individualized treatments. As the health care providers of the future, today’s students will be diagnosing and treating patients based on a barrage of information not just about the person in front of them, but also about millions of other patients around the world.

UCSF pharmacy student Julia Choi received genetic testing in one of her courses, an experience that she says was intensely personal – and important training for her future as a pharmacist.

UCSF pharmacy student Julia Choi received genetic testing in one of her courses, an experience that she says was intensely personal – and important training for her future as a pharmacist.

Genetic codes; environmental and nutritional data; reports from patients’ electronic health care monitors; and input from epidemiologists, informaticians and scientists studying the molecular underpinnings of disease – all these factors must be considered in the world of precision medicine. The upside is that “we will be able to find the right treatment for our patients, without going through all the trial and error we do today,” says Catherine Lucey, M.D., a resident alumna and the vice dean for education at UCSF School of Medicine.

“What’s so great about being at UCSF is that we’re fortunate enough to have people who strive to practice tomorrow’s medicine today,” she continues. The university has been educating its students regarding precision medicine for years by teaching them about genetics, population-based clinical research, and the nature and importance of working in multidisciplinary teams.

As Choi learned firsthand in the School of Pharmacy’s Genetics and Pharmacogenetics course, a single gene can influence drug response – knowledge that is shaping more precise approaches to therapeutics.

She was one of 22 out of 122 students in her class to opt in for the genetic testing, which evaluated the CYP2C19 enzyme. People who have variants of this enzyme can over- or under-metabolize clopidogrel (also known by the brand name Plavix), which means they are 3.6 times more likely to suffer a heart attack, stroke, or even death. These outcomes can be easily avoided, however, by first testing a patient for the genetic mutations and then prescribing a higher or lower dose of the drug or another drug entirely.

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UCLA team first to map autism-risk genes by function


Results reveal how mutations in genes disrupt early brain development.

Daniel Geschwind, UCLA

Daniel Geschwind, UCLA

Pity the poor autism researcher. Recent studies have linked hundreds of gene mutations scattered throughout the brain to an increased risk for autism. Where does one start investigating?

UCLA neuroscientists may have an answer. They are the first to map groups of autism-risk genes by function and to identify where and when these genes affect early brain development.

In addition, they discovered disturbances in neural circuits that define key pathways between parts of the cerebral cortex that are known to be involved in autism. The research suggests that these disruptions are created by mutations in genes during fetal brain development and are not a result of autism itself.

Published in the Nov. 21 edition of Cell, the findings shed light on how genetic changes cause autism on a molecular level and will help prioritize targets for future studies.

“Identifying gene variants that boost risk is only the first step of unraveling a disease,” said lead author Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, professor of neurology at the David Geffen School of Medicine at UCLA and professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior. “We need to figure out where genetic changes appear in the brain, at what stages during development they occur and which biological processes they disrupt. Only then will we understand how mutations cause autism.”

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Fast-mutating DNA sequences shape early development


Study reveals new insight into origins of our species.

Katherine Pollard

Katherine Pollard

What does it mean to be human? According to scientists the key lies, ultimately, in the billions of lines of genetic code that comprise the human genome.

The problem, however, has been deciphering that code. But now, researchers at the Gladstone Institutes have discovered how the activation of specific stretches of DNA control the development of uniquely human characteristics – and tell an intriguing story about the evolution of our species.

In the latest issue of Philosophical Transactions of the Royal Society B, researchers in the laboratory of Gladstone investigator Katherine Pollard, Ph.D., use the latest sequencing and bioinformatics tools to find genomic regions that guide the development of human-specific characteristics. These results offer new clues as to how the activation of similar stretches of DNA – shared between two species – can sometimes result in vastly different outcomes.

“Advances in DNA sequencing and supercomputing have given us the power to understand evolution at a level of detail that just a few years ago would have been impossible,” said Pollard, who is also a professor of epidemiology and biostatistics at UC San Francisco’s Institute for Human Genetics. Gladstone is affiliated with UCSF.

“In this study, we found stretches of DNA that evolved much more quickly than others,” she said. “We believe that these fast-evolving stretches were crucial to our human ancestors becoming distinct from our closest primate relatives.”

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