New Test Spots Early Signs of Inherited Metabolic Disorders
A team of scientists, led by researchers at the University of California, San Diego School of Medicine and Zacharon Pharmaceuticals, have developed a simple, reliable test for identifying biomarkers for mucopolysaccharidoses (MPS), a group of inherited metabolic disorders that are currently diagnosed in patients only after symptoms have become serious and the damage possibly irreversible.
MPS is caused by the absence or malfunctioning of a lysosomal enzyme required to break down and recycle complex sugar molecules called glycosaminoglycans, which are used to build bone, tendons, skin and other tissues. If not degraded and removed, glycosaminoglycans can accumulate in cells and tissues, resulting in progressive, permanent damage affecting appearance, physical abilities, organ function and often mental development in young children. The effects range from mild to severe.
There are 11 known forms of MPS, each involving a different lysosomal enzyme. A number of treatments exist, including enzyme replacement therapy and hematopoietic stem cell transplantation, but efficacy depends upon diagnosing the disease and its specific form as early as possible. That has been problematic, said Jeffrey D. Esko, PhD, professor in the Department of Cellular and Molecular Medicine and co-director of the Glycobiology Research and Training Center at UC San Diego.
“The typical time from seeing first symptoms to diagnosis of MPS is about three years. Since the early signs of disease are common childhood issues like ear infections and learning disorders, the disease is usually not immediately recognized,” Esko said.
“A child often has multiple visits with their pediatrician. Eventually they are referred to a metabolic disease specialist, where rare diseases are considered. It takes an expert to identify MPS and its most likely form in each patient. Every subclass of MPS has its own specific diagnostic test, so developing better diagnostics is an essential part of effective treatment. ”
Rare Genetic Mutations Linked To Bipolar Disorder
An international team of scientists, led by researchers at the University of California, San Diego School of Medicine, reports that abnormal sequences of DNA known as rare copy number variants, or CNVs, appear to play a significant role in the risk for early onset bipolar disorder.
CNVs are genomic alterations in which there are too few or too many copies of sections of DNA. Researchers have known that spontaneously occurring (de novo) CNVs – genetic mutations not inherited from parents – significantly increase the risk for some neuropsychiatric conditions, such as schizophrenia or the autism spectrum disorders. But their role was unclear in bipolar disorder, previously known as manic depression.
Principal investigator Jonathan Sebat, PhD, assistant professor of psychiatry and cellular and molecular medicine at UC San Diego’s Institute of Genomic Medicine, and colleagues, found that de novo CNVs contribute significant genetic risk in about 5 percent of early onset bipolar disorder, which appears in childhood or early adulthood.
Cognitive consilience
More than a century ago, a Spanish pathologist named Santiago Ramon y Cajal produced a series of highly detailed drawings of the microscopic structures of the human brain. It marked the beginning of modern neuroanatomy and ultimately helped earn Cajal a share of the 1906 Nobel Prize for medicine (with Italian anatomist Camillo Golgi.
Cajal’s drawings remain a marvel and are still widely used, but advances in neuroscience demand new ways to look at – and understand – how the human brain is structured and how it functions.
A recent PhD graduate and a post-doc at the University of California San Diego – Soren Solari in the Department of Mechanical and Aerospace Engineering and Rich Stoner in the Department of Neurosciences - have created a modern take on Cajal’s pioneering work.
Publishing in the journal Frontiers in Neuroanatomy, Solari and Stoner have created a detailed review of cortical circuitry, along with a first-of-a-kind interactive website and an iPhone/iPad application that allows scientists to navigate aspects of the human brain.
“We wanted to create an interactive Figure 1,” said Stoner, who currently conducts research at the UC San Diego Autism Center of Excellence. “Readers of the review are able to click on a circuit and quickly find an accompanying reference.”
To build the tool, Solari and Stoner synthesized seven hypothetical circuits of the brain from scores of published neuroanatomy papers into a single interactive map that depicts consolidated long-term declarative memory, short-term declarative memory, working memory/information processing, behavioral memory selection, behavioral memory output, cognitive control and cortical information flow regulation. The map is built on data derived from multiple mammalian models.
“It’s the first coherent view of cortical circuits across different scales from different sources,” said Stoner. “We use the term ‘cognitive consilience’ because it’s about bringing together a lot of different information to form a coherent picture. It’s the unity of knowledge.”
By clicking on different links within each depicted circuit, users can read brief descriptions of the visualized cells and structures. The information is not definitive, of course. Solari and Stoner say they have erected this first iteration as a model for future researchers to add new information. “We’d like to see this become a viable tool for scientists to describe their work,” said Stoner.
Life as we grow it
When the news was reported in May 2010, some of the first headlines were not surprisingly sensational: “Scientist accused of playing God after creating artificial life by making designer microbe from scratch - but could it wipe out humanity?” screamed The Mail in the UK.
Obviously a bit breathless and over-the-top, but J. Craig Venter’s announcement that he and colleagues had created a “synthetic cell” by inserting a chemically constructed genome into a Mycoplasma bacterium, and then inducing it to successfully propagate, was – and is – a notable achievement. “This is a philosophical advance as much as a technical advance,” Venter told The New York Times, suggesting that the work (published in Science) raised new questions about the nature of life.
Just how notable or paradigm-shifting Venter’s creation proves to be remains to be seen. The synthetic organism, seen above in this scanning electron micrograph produced by Tom Deerinck and Mark Ellisman at NCMIR, is inarguably a technical feat. Venter and colleagues synthesized a million units of bacterial DNA and got them to functionally replace the bacterium’s natural counterparts. “This is the first synthetic cell that’s been made, and we call it synthetic because the cell is totally derived from a synthetic chromosome, made with four bottles of chemicals on a chemical synthesizer, starting with information in a computer,” said Venter.
Ultimately, the goal is to achieve complete control over a bacterium’s genome so that researchers can routinely remove, replace and rearrange genes to create new microorganisms capable of unprecedented functions, such as gobbling oil spills or secreting drugs.
That day hasn’t arrived. The editors at The Mail can relax. Humanity remains safe.
DNA repair
DNA mismatch repair (MMR) is the body’s system for recognizing and fixing mispaired bases (adenine with thymine, guanine with cytosine) that occur during genetic replication and recombination. It’s a vital process because it eliminates mutations that can result in defects and the development of different cancers.
It’s also a bit of a mystery, in part because no one has ever actually seen the system at work. Until now. In a paper published in the November 23 issue of the journal Cell, Richard Kolodner, PhD, a member of the Ludwig Institute for Cancer Research, professor of medicine and member of the Moores Cancer Center at UC San Diego School of Medicine and colleagues use fluorescent visualization techniques to show what’s happening in vivo for the first time.
The researchers studied live cells of Saccharomyces cerevisiae, or Baker’s yeast. “MMR in yeast and humans is exactly the same,” said Kolodner. “Yeast and humans use the same proteins and the repair process involves the same steps in each organism.”
They focused on the Msh2-Msh6 and Mlh1-Pms1 protein complexes, known to play a role in MMR. “We saw that the MMR protein that detects errors in the DNA linked to the proteins that replicate the DNA,” said Kolodner. “We also saw that when the first MMR protein encountered an error in the DNA, it assembled a second MMR protein onto the DNA to initiate the repair process.”
The discovery reveals for the first time a key mechanism used by MMR proteins to find individual damaged sites in DNA among the vast numbers of non-damaged DNA sites in a cell. Having a better understanding of how DNA is repaired could ultimately lead to future therapies to assist the process or treat existing cancers.
“Inherited defects in MMR genes cause one of the most common forms of inherited cancer susceptibility known,” said Kolodner. “In addition, a significant number of non-inherited cancers have MMR defects that play a role in their development. And sometimes in cancers that have become resistant to chemotherapy, the acquired resistance is due to selection for a MMR defect during treatment.”
Co-authors of the paper with Kolodner were Arshad Desai, Catherine E. Smith, Christopher S. Campbell and Hans Hombauer, all at the Ludwig Institute and UC San Diego School of Medicine.
In this artist’s rendering of a working capillary, various constituents of human blood (red blood cells, platelets, macrophages, etc.) are carried along by flowing plasma.
Looking at lipids
By and large, when most people think about lipids, they think about fats – and probably not very kindly. But lipids are much more than just fats. They are a broad group of naturally occurring molecules that also includes oils, waxes, acids and sterols. And they do a lot things to sustain and promote life; their roles extending well beyond that stuff you see hanging over your belt after a belly-busting Thanksgiving dinner.
In the November 10 issue of The New England Journal of Medicine, Edward A. Dennis, PhD, distinguished professor of pharmacology, chemistry and biochemistry at the University of California, San Diego School of Medicine, and Oswald Quehenberger, PhD, professor of medicine, describe the human plasma lipidome, that vast and vastly diverse assemblage of lipids circulating in human blood.
Human plasma is the straw-colored liquid in which blood cells in whole blood are normally suspended. It’s mostly water (93 percent) but also contains nucleic acids, amino acids, carbohydrates and, of course, lipids.
Much is known about the first three. There are only two basic types of nucleic acid (DNA and RNA), 20 amino acids and perhaps a few hundred kinds of carbohydrate or saccarhide (sugar molecules). Conversely, lipid types number in thousands, possibly hundreds of thousands. A paper by Dennis, Quehenberger and colleagues last year found almost 600 distinct species in human plasma alone.
Historically, lipids have been hard on a grand scale. Beyond myriad numbers, they come in myriad shapes. The on-going LIPID MAPS project, a national consortium based at UC San Diego and headed by Dennis, is the first effort to do just that.
Their wildly varied physical attributes give hint of lipids equally diverse functions.
Cholesterol, for example, is the most abundant sterol lipid in human plasma. There are more than 22 distinct molecular species. It’s notorious, of course, for its association with cardiovascular risk, but cholesterol is also essential to life. It’s used to make hormones and establish proper permeability and fluidity of cell walls.
Glycerophospholipids constitute the main components of cell membranes and serve as precursors for signaling molecules in many cellular and physiological processes. Cancer cells have malfunctioning glycerophospholipids, which makes them a potential target for future anticancer therapies. Indeed, many oncological processes – cell proliferation, survival, migration, invasion and angiogenesis – deeply involve lipids, making them concordant with these hallmarks of cancer.
Sphingolipids are plentiful in nervous tissue. Some have potent messenger functions and are involved in directing immune cells, maintaining vascular tone and promoting cell communication in the central nervous system. When they don’t work well, certain autoimmune diseases like multiple sclerosis may result. Sphingolipids are also implicated in a variety of neurological diseases, coronary heart disease and type 2 diabetes.
The sheer abundance of lipid metabolites in human plasma makes them an obvious target for researchers seeking biomarkers of disease and treatment. Levels of specific lipid species may be able to provide tell-tale diagnoses of unhealthy conditions or the future possibility of them. For example, a recent meta-analysis of genomewide associations involving more than 100,000 people identified 95 distinct gene variants linked to lipid traits in plasma that affect blood lipid levels and have direct relevance to cardiovascular disease.
Dennis’ and Quehenberger’s review article in NEJM goes into some detail to explain and extol the scientific value and therapeutic potential of lipids. They acknowledge there’s much work to be done. It was only recently, for example, that researchers published the first functioning lipidome of a mouse macrophage or white blood cell. It involved more than 400 molecular lipid species.
Given the role lipids play role in many metabolic diseases and burgeoning health conditions, including type 2 diabetes and obesity, progress can’t happen soon enough.
An MRI depicts a glioblastoma (center white mass) before treatment with the drug erlotinib (A) and after (B).
Old Drugs Find New Target For Treating Brain Tumor
Scientists at the University of California, San Diego School of Medicine and UC San Diego Moores Cancer Center, in collaboration with colleagues in Boston and South Korea, say they have identified a novel gene mutation that causes at least one form of glioblastoma (GBM), the most common type of malignant brain tumor.
Past studies have identified epidermal growth factor receptor (EGFR) as a common genetically altered gene in GBM, though the cause or causes of the alteration is not known. The research team, led by scientists at the Dana-Farber Cancer Institute in Boston, analyzed the GBM genomic database, ultimately identifying and characterizing an exon 27 deletion mutation within the EGFR carboxyl-terminus domain (CTD). An exon is a segment of a DNA or RNA molecule containing information coding for a protein or peptide sequence.
“The deletion mutant seems to possess a novel mechanism for inducing cellular transformation,” said Frank Furnari, PhD, associate professor of medicine at the UC San Diego School of Medicine and an associate investigator at the San Diego branch of the Ludwig Institute for Cancer Research.
The study researchers determined that cellular transformation was induced by the previously unknown EGFR CTD deletion mutant, both in vitro and in vivo, and resulted in GBM in the animals. The researchers then turned to testing a pair of approved drugs that target EGFR: a monoclonal antibody called cetuximab and a small molecule inhibitor called erlotinib.
New Drug Combo Targets Multiple Cancers
Sugar molecule primes cancer cells for early death from second compound
Researchers at the University of California, San Diego School of Medicine and Kyushu University Medical School say a novel combination of a specific sugar molecule with a pair of cell-killing drugs prompts a wide variety of cancer cell types to kill themselves, a process called apoptosis or programmed cell death.
The findings are reported online in the journal Cancer Research.
“The goal of targeted therapy is to stop the growth of cancerous cells while doing little or no harm to healthy tissue,” said Guy Perkins, PhD, associate project scientist at the Center for Research in Biological Systems at UC San Diego. “Cancer researchers are always looking for new therapies to target a variety of cancers and kill tumor cells in various stages of development.”
Unfortunately, added co-author Ryuji Yamaguchi, PhD, senior researcher at Kyushu University Medical School in Fukuoka, Japan, “even the best new drugs seem to be limited to specific cancer types and too often tumor cells develop resistance to these drugs, leading to eventual treatment failure.”
Color-coded representations of human and mouse brains show similarities in cortical functional organization, with some variance according to species-specific needs. F/M indicates the frontal/motor cortex; S1, primary somatosensory cortex; A1, auditory cortex and V1, visual cortex.
Of Mice and Men, a Common Cortical Connection
MRI study finds genetic basis of brain development largely similar in mice and humans
A new study using magnetic resonance imaging data of 406 adult human twins affirms the long-standing idea that the genetic basis of human cortical regionalization – the organization of the outer brain into specific functional areas – is similar to and consistent with patterns found in other mammals, indicating a common conservation mechanism in evolution.
The findings by researchers at the University of California, San Diego School of Medicine and colleagues are published in the November 17 issue of the journal Neuron.
Past animal studies, primarily in rodents, have shown that development of distinct areas of the cortex – the outer layer of the brain – is influenced by genes exhibiting highly regionalized expression patterns. The new study is among the first to confirm these findings using data from human subjects. As in other mammals, the researchers found that that genetic influences in human brain development progress along a graduating scale anterior-to-posterior (front-to-back) in a bilateral, symmetric pattern.
There were, of course, differences based upon the particular needs and functions of each species.
Blood Pressure and Stroke Risk Gets More Complicated
Low systolic blood pressure may actually boost chances of recurrent stroke.
For patients who have suffered an ischemic stroke, traditional treatment prescribes keeping subsequent blood pressure levels as low as possible to reduce the risk of another stroke. A new international study, however, suggests this conventional approach may not be helpful, and could actually increase recurrent stroke risk – at least in the first few months after the first event.
The 5-year study examined the cases of 20,330 patients (age 50 years and older) at 695 centers in 35 countries who had suffered a recent non-cardioembolic ischemic stroke, which is caused by drifting blood clots formed outside of the heart. Patients were categorized by their average Systolic blood pressure (SBP) level: very low-normal (less than 120 mmHg), low-normal (120 to less than 130 mm Hg), high-normal (130 to less than 140 mm Hg), high (140 to less than 150 mm Hg) and very high (150 mm Hg or greater).
