Human-Chimp Evolutionary Divergence: Methylation and Gene Sequence Co-Evolved
September 19, 2011
Scientists at Cold Spring Harbor Laboratory (CSHL) and the University of Southern California (USC) have published the first quantitative evidence supporting the notion that the genome-wide "bookmarking" of DNA with methyl molecules -- a process called methylation -- and the underlying DNA sequences corresponding with these marks, have co-evolved in a kind of molecular slow-dance over the 6 million years since humans and chimps diverged from a common ancestor.
The team's findings in some ways defy the conventional understanding of how methylation and related processes work. Broadly known as epigenetic processes, methylation and other means by which the genome is "marked" are usually thought of as altering the way a gene is expressed (i.e., whether it is "on" or "off") without changing the underlying sequence of DNA letters -- As, Gs, Cs and Ts -- that "spell out" the gene.
Yet the new research supports theories proposing that methylation changes could drive changes in DNA sequence. The CSHL-USC team specifically suggests that methylation changes, which are reversible, might allow a short-term "flexibility in phenotype" -- characteristics that individuals within a species exhibit -- that would be a kind of dry run for more permanent genomic changes, if a newly conferred trait proves advantageous.
"This part of our data shows how it is possible for methylation to serve as an agent of evolution," says the co-leader of the research team, Dr. Gregory Hannon, a CSHL Professor and an Investigator of the Howard Hughes Medical Institute. The second team leader is Dr. Andrew Smith, a USC Professor and lab head, who began the project with Hannon while doing postdoctoral research at CSHL several years ago.
The evolutionary insight about methylation is only one of a number of new perspectives that emerge from the team's research paper, which is the cover story in the September 16 issue of the journal Cell. Its publication coincides with advance publication of a sister paper in Molecular Cell by the same team, whose members also include CSHL Professor W. Richard McCombie and co-first authors of the paper, CSHL postdoc Dr. Emily Hodges and doctoral student Antoine Molaro. Hodges is lead author of the companion paper, which shows how methylation changes in human blood stem cells are involved in "cell-fate decisions" that help determine how the precursor cells differentiate into mature lineage-specific blood cells.
Cells are reprogrammed in two waves
The project set out to explore one of the most fascinating phenomena in all of biology. Twice in the lives of mammalian cells, DNA is wiped completely clean of epigenetic markings and then reprogrammed. The purpose of this process of erasure and reinscription is still rather mysterious. Only once before has the full set of methyl marks -- called the "methylome" -- been sequenced in humans with single-nucleotide resolution on a genome-wide basis. The new work sets those results in comparative perspective with the methylomes of another class of cells in humans and chimps, by looking for patterns of similarities and differences.
Each of the two cell types studied represents the "output" of one of the two reprogramming waves. One type was human embryonic stem (ES) cells; this cell type is the progenitor of all so-called "somatic" cells, i.e., cells that "differentiate" into all the tissues and organs of an organism. The methylome of the ES cells used in the current study was generated in a previous study. It is used in the current study for comparative purposes, specifically, to form a comparison with male germs cells sampled from two humans and from two chimpanzees, man's closest evolutionary relative.
"These two cell types, the human ES cell and the human and chimp male germ cell, represent the output of the two re-programming waves, and as such are the basis or 'ground state' for all that will follow, over the life of the individual cell and the organism itself," explains Molaro. "The ES cells subsequently differentiate into lung, blood, heart, liver, brain cells, etc. The germ cells are of course fundamental to sexual reproduction."
Methylation in different cell types vs. within types across species
It has long been known that methylation marks are among the most important factors in determining how a given cell will develop within a given organism and how it will behave once mature. For instance, it is believed that methylation has a great deal to do with how a given stem-like precursor cell "knows" which genes to switch on in order to become a liver cell and not a heart cell, or a brain cell and not a lung cell.
The current study provides the first quantitative evidence of a remarkable fact: the methylation patterns that characterize each class of human or chimp cells -- heart, blood, liver, etc. -- are far more different from one another than are the patterns within each cell type when viewed across species. A chimp heart cell will share most of its methylation marks with a human heart cell; but the chimp heart cell's methylation patterns will share comparatively fewer points of commonality when compared with those seen in a chimp's liver cells.
This fact lends quantitative support to the known fact that methylation helps define cell types. But this and other evidence in the research also says something that until now has been purely speculative: by looking very closely at methylation patterns within individuals and across species, one can begin to piece together previously hidden stories about how species grew apart via evolution.
Humans and chimps diverged from their common ancestor about 6 million years ago. That is a very short period on the timescale of evolution, which on our planet began at the point nearly 4 billion years ago when the first self-replicating cells appeared.
The default state for both genomes, chimp and human, is for a given spot capable of methylation to in fact be methylated, according to Hannon. Methylation, when it occurs, involves a chemical process at positions across the genome where a cytosine base is followed by a guanine base -- so called CpG sequences. Methyl groups (CH3) attach to the cytosine in such sequences, and do so between 70% and 80% of the time, across both chimp and human genomes.
Comparison of non-methylated regions, across species
The CSHL-USC team derived its most important information based on a close analysis of clusters of CpG sequences in which methylation does not occur. Successive unmethylated CpGs form what are called hypomethylated regions, or HMRs. The team found these to be structurally different in ES cells and sperm cells, within species, and continue to seek an explanation.
HMRs have long been of interest because the DNA sequences of most of the 21,000 human genes are associated with HMRs. Therefore, HMRs -- areas without methyl marks -- have been used as a rough guide to where genes lie in the vast DNA landscape that is the genome, 98% of which does not consist of genes.
More specifically, most HMRs overlap with the very beginning portions of gene sequences in humans and chimps -- places called promoters. This fact is of evolutionary import: places in the genome where genes are regulated tend to be unmethylated. This is the flip side of a fact that has long been known: methylation tends to block gene expression. One way is by blocking access of the cell's transcriptional machinery at promoter sites.
Hannon, Smith and colleagues propose methylation is a potential agent of evolution by applying sophisticated analytic algorithms to small changes in the human vs. chimp methylomes. They cite, in one of several examples, a gene called HTR3E, which encodes a structural unit of a serotonin-receptor protein that is expressed in cells of the nervous system. The gene is found in humans and chimps. But at the site of its promoter, the methylation pattern differs: in humans, the promoter is not methylated and in chimps it is methylated.
The functional significance of this difference cannot be determined on the basis of this information alone. The data is important, however, as one example among many where differences in methylation status between closely related species may provide clues about how adaptive pressure acted differently upon each. A broadening of the work done by the CSHL-USC team to include other species will be needed, says Hannon, in order to shed further and more definitive light on the mutual interactions of genome and epigenome in evolution, over the short and long term.
This work was supported by grants from the National Institutes of Health and by a kind gift from Kathryn W. Davis.
Team Discovers Treatable Mechanism Responsible for Often Deadly Response to Flu
September 19, 2011
Researchers at The Scripps Research Institute have found a novel mechanism by which certain viruses such as influenza trigger a type of immune reaction that can severely sicken or kill those infected.
This severe immune reaction -- called a "cytokine storm" -- floods the tiny air sacs of the lungs with fluid and infection-fighting cells, blocking off airways and damaging body tissues and organs. Cytokine storms are believed to have played a major role in the staggering mortality of the 1918-1919 worldwide influenza pandemic, as well as in the more recent swine flu and bird flu outbreaks.
In a new study published in the September 16, 2011, issue of the journal Cell, a team of Scripps Research scientists have pinpointed the cells that orchestrate cytokine storms, opening up entirely new possibilities for treatment of the condition.
"In the new research, we show directly for the first time that the damaging effects of cytokine storm are distinct from the impact of virus replication and pathological changes in infected cells," said Scripps Research Professor Hugh Rosen, MD, PhD, who led the study with Scripps Research Professor Michael B.A. Oldstone, MD. "The findings provide a new paradigm for understanding influenza and could point the way to new therapies."
"This study has greatly increased our understanding of the biological basis of cytokine storm, opening the door to development of new treatments for this potentially fatal immune reaction," said James M. Anderson, MD, PhD, director of the National Institutes of Health (NIH) Division of Program Coordination, Planning, and Strategic Initiatives, which provided funds for the work. "This research is an excellent example of scientific discovery facilitated by the NIH Common Fund's Molecular Libraries and Imaging program and of the potential that this discovery provides for targeted new therapies."
New Approach to an Old Foe
Influenza and many other viruses destroy cells, especially the cells that line the alveoli (tiny air sacs) that exchange gases in the lung. In response, the body generates cytokines (small cell-signaling protein molecules) and brings in a variety of immune cells in an attempt to limit infection. Normally, the production of cytokines is kept in check by the body, but in some cases cytokine production goes into overdrive and results in a dangerous cytokine storm.
Using advanced chemical and genetic approaches that allow tracking and modulation of receptor function in real time, the Scripps Research team set out to determine the role of a receptor S1P1 (molecule on the surface of a cell that binds to molecules, triggering a certain biological effect) for a specific molecule known as Sphingosine-1-phosphate (S1P). S1P1 has been a topic of investigation in Rosen's lab, in part due to its connection to autoimmune disease.
Unexpectedly, the team found that manipulating the S1P1 receptors in the endothelial cells -- the thin layer of cells lining the interior surface of blood vessels -- in the lung affected cytokine release. Previously, scientists had assumed that cytokine release occurred through virus-infected cells or other cells lining the lungs.
Next, the scientists wanted to see if they could alter the course of cytokine storm in mice infected with the human pandemic influenza strain that resulted in a severe flu season in 2009 (H1N1 2009). Using a molecule that bound to the S1P1 receptor, the team was able to "downregulate" the immune reaction, allowing enough immune response to fight the virus, while at the same time diminishing or even eliminating the cytokine storm and improving survival rate from infection.
"It had been thought for a long time that all injury from influenza was due to the virus itself, consequently, and rationally, the focus was on developing antiviral drugs," said Oldstone. "The surprise in our findings was that by modulating the S1P1 receptors, we could protect the infected host, a target not subject to the rapid mutational escape of the virus, and therefore less subject to resistance."
Looking to the Future
A number of companies including Novartis, Actelion, and Receptos have S1P1 modulators in clinical trials. The Receptos compounds were discovered by the Rosen and Roberts laboratories in the Scripps Research Institute Molecular Screening Center, supported by the NIH Common Fund.
"Now that we know where cytokines come from and have isolated the specific receptor-based mechanism, it is likely that a single oral dose of a compound can be developed that will provide protection from cytokine storm early in infection," said Rosen, who added that previous studies from his lab suggested that such a drug could be used in conjunction with Tamiflu, a common antiviral medication used to treat influenza.
Oldstone noted that future research on the S1P1 receptor could help identify which individuals are most susceptible to cytokine storms and would be most likely to benefit from a drug targeting this mechanism.
The joint first authors of the study, "Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection," were Scripps Research postdoctoral fellows John Teijaro and Kevin Walsh. Additional authors included Stuart Cahalan, Daniel M. Fremgen, Edward Roberts, Fiona L. Scott, Esther Martinborough, and Robert J. Peach.
The study was supported by grants from the United States Public Health Service and the National Institute of Allergy and Infectious Diseases, part of the NIH, and the NIH Common Fund.
Fail-Safe System May Lead to Cures for Inherited Disorders
September 19, 2011
Scientists at the University of California, San Diego School of Medicine have uncovered a previously unknown fail-safe (compensatory) pathway that potentially protects the brain and other organs from genetic and environmental threats. The discovery could provide new ways to diminish the negative consequences of genetic mutations and environmental toxins that cause neurological diseases and other maladies.
The findings are published in the Sept. 16 issue of the journal Molecular Cell.
Messenger ribonucleic acid (mRNA) is an essential molecule that "reads" genetic information contained within the human genome, and based on this information, generates proteins essential for life. A key inherent feature of mRNA is its "stop signal," which tells cellular machinery to stop reading the mRNA because it has produced a full-length protein. Importantly, in some aberrant mRNAs, the stop signal is displayed too early, resulting in the production of a shorter-than-normal protein. Some of these short proteins can be highly toxic to cells. To avoid their production, cells use a quality control pathway called nonsense-mediated mRNA decay or NMD, which rapidly degrades "bad" mRNAs with early stop signals.
In research published earlier this year, Miles Wilkinson, PhD, professor of reproductive medicine and a member of the UCSD Institute for Genomic Medicine, and colleagues, revealed that NMD is important for the normal development of the brain and the nervous system. Jozef Gecz, PhD, professor of pediatrics at the University of Adelaide, showed that when NMD doesn't work correctly, neurological conditions arise, ranging from mental retardation and attention-deficit disorder to schizophrenia and autism. These conditions are likely due to the production and accumulation of short proteins in the brain.
Like all components of the body, the NMD pathway is vulnerable to insults, such as environmental toxins or gene mutations. "If such events prevent the NMD pathway from working, there will be an accumulation of short proteins, some of which are likely toxic, resulting in bad consequences to the individual," Wilkinson said.
In their present work, Wilkinson and colleagues report the discovery that human cells have evolved a way to overcome attacks on the NMD pathway. If any molecule of the pathway is injured, the cell sends reinforcement molecules to compensate for the loss.
"These reinforcements are not sent out from all cells of our body but only selectively in certain cells; in some cases they appear to be sent from cells that need reinforcements the most," Wilkinson said.
"This is an important feature of this compensatory ("buffering") response that could potentially be relevant for clinical application," Wilkinson said. "To appreciate this, one first needs to realize that a very large proportion of people with genetic diseases -- one-third, in fact -- have a faulty gene with a mutation that leads to an early stop signal. As a consequence, most of these genes will give rise to an mRNA that is degraded by NMD and hence the encoded protein is never made. A key point is that a proportion of these mutant proteins -- although shorter than normal -- is actually still functional. So, if clinicians could inhibit NMD, this would potentially ameliorate the symptoms of some of these diseases because this treatment would increase the production of these short, but still functional, proteins."
"Unfortunately, a global NMD blockade would also lead to the production of lots of other short proteins, some of which would be toxic," Wilkinson noted. As a result, "in the past, there has been little interest in 'NMD-inhibition therapy.'" The new discovery makes NMD-inhibition therapy much more attractive because the tissue-specific compensatory response has the potential to greatly dampen the side effects. "By choosing a branch of the NMD pathway that is subject to compensation only in the appropriate tissues, a highly selective effect can potentially be achieved" said Wilkinson.
"For example, there is a need to come up with better treatments for cystic fibrosis -- a heritable chronic lung disease -- that is currently being treated in some patients with drugs that act by blocking recognition of the premature stop signal in the mutant CFTR gene," he said. "There has been some success with this approach, but there are concerns with side effects." The finding that NMD is buffered by a tissue-specific regulatory system means that one could design a different type of drug -- a tissue-specific NMD-inhibition drug -- that increases the level of the CFTR protein primarily in its main cellular site of action: the lung. "This could potentially increase the efficacy and drastically reduce the side effects of NMD-inhibition drugs" says Wilkinson.
Lead author of the study is Lulu Huang, with co-authors Chih-Hong Lou, Wai-kin Chan, Eleen Y. Shum, Hye-Won Song, Ada Shao and Rachid Karam in the Department of Reproductive Medicine, UCSD School of Medicine. Also contributing is Erica Stone in the Department of Cellular and Molecular Medicine at UCSD.
Funding for this work came from the National Institutes of Health.
Some Like It Hot: European Fish Stocks Changing With Warming Seas
September 19, 2011
The first "big picture" study of the effects of rapidly rising temperatures in the northeast Atlantic Ocean shows that a major shift in fish stocks is already well underway. But it isn't all bad news. The research, published Sept. 15 in Current Biology, shows that some fishes' losses are other fishes' gain.
The study, led by Dr Steve Simpson of the University of Bristol in collaboration with researchers from eight other institutions, is the first to combine a suite of European datasets, which included more than 100 million fish, to explore how warming is affecting the commercially important European fishery. The researchers analysed 28 years of fisheries agency data from 11 independent surveys covering more than a million square kilometres of the European continental shelf.
The northeast Atlantic has been described as the "cauldron of climate change," with warming occurring at a rate four times the global average over the past 30 years. Dr Simpson, a researcher in the University's School of Biological Sciences, explained: "While a 1.3° Celsius change in mean annual temperature in the North Sea over the past three decades may sound trivial, temperature has a strong influence on egg maturation rates, growth and survival of fish larvae, and impacts on the planktonic communities that underpin the food webs that sustain commercial fisheries.
"We see many more southerly warm-water species faring well on the European shelf than northerly cold-adapted species. This means more small-bodied, faster growing species with shorter generation times, and potentially more diversity."
Indeed, the data show that fish in European waters have undergone profound community-level changes that are related to dramatic warming trends for the region. The vast majority -- a whopping 72 percent -- of common fish species have already shown a change in abundance that relates to the rising sea temperatures.
Of those, three out of every four fish species have grown in numbers with warming. Catches of cold-loving species, including haddock and cod, have dropped by half in the past three decades, whereas landings of warm-loving species, including hake and dab, have more than doubled.
The results show that studies focused only on changes to where particular fish species are found -- species ranges -- will miss the far more ecologically and economically relevant effects of warming. They also suggest there will be an unavoidable change in what's for dinner.
Simpson added: "We may see a further decline in cold-adapted species, many of which were the staple for our grandparents. The flip side is a likely increase in species that for the UK may seem relatively exotic now, such as red mullet and John Dory. Over time, with effective management and an appropriate response in consumer demand, European seas have the potential to yield productive and sustainable fisheries into the future."
Carbon Nanoparticles Break Barriers -- And That May Not Be Good
September 19, 2011
A study by researchers from the schools of science and medicine at Indiana University-Purdue University Indianapolis examines the effects of carbon nanoparticles (CNPs) on living cells. This work is among the first to study concentrations of these tiny particles that are low enough to mimic the actual exposure of an ordinary individual.
The effects on the human body of exposure to CNPs -- minute chemicals with rapidly growing applications in electronics, medicine, and many other fields -- is just beginning to be revealed. Exposure at the level studied by the IUPUI researchers is approximately equivalent to what might be the result of improperly disposing of an item such as a television or computer monitor containing CNPs, living near a CNP producing facility, or working with CNPs.
The research, published in the September 2011 issue of the journal Nanotoxicology, focuses on the effect of low concentration CNP exposure on the cells that line the renal nephron, a tubular structure inside the kidney that makes urine. The investigators found the role of the CNPs in this part of the body to be significant and potentially worrisome.
"Unlike many other studies, we have used low concentrations of CNPs that are typical of what might appear in the body after ingesting them from environmental contamination or even from breathing air with CNPs. We found that these minute particles cause leakage in the cellular lining of the renal nephron," said study first author Bonnie Blazer-Yost, Ph.D., professor of biology at the School of Science at IUPUI and adjunct professor of cellular and integrative physiology and of anatomy and cell biology at the IU School of Medicine.
"Breaching this biological barrier concerns us because things that should be retained in the forming urine can leak back into the blood stream and things in the blood can leak into the urine. Normal biological substances as well as waste products are dangerous if they go where they are not supposed to be," Blazer-Yost said.
"These CNPs don't kill cells -- so they are not lethal, but they do affect cells, and in this case it's an adverse effect," said corresponding and senior author Frank Witzmann, Ph.D., professor of cellular and integrative physiology and of biochemistry and molecular biology at the IU School of Medicine and adjunct professor of biology at the School of Science.
Biological barriers are very important to human health. The most well understood is the skin, but there are many others. "The human body needs intact barriers, whether it be skin, airway linings, gut walls or the kidney cells we looked at in this study. We need to gain a better understanding of how CNPs modify and change characteristics of barriers as these tiny particles become more common in the air we breathe," said Witzmann.
The two researchers note that these incredibly strong particles, visible only under an electron microscope, perform useful functions including roles in drug delivery and are responsible for many advances in electronics such as the impressive colors seen on plasma televisions and computer monitors. What they worry about is when CNPs enter the air and the environment and eventually the human body from inappropriate disposal or from manufacture of products containing the particles.
This study is part of the team's larger body of work, which looks at the effect of CNPs on barriers throughout the body including those of the airways and large intestine.
"At this point, we know that CNPs have many beneficial qualities, but also pose potential risks. These particles are so small that when they get into various organs or systems they can bind to many things. We need to further study what they look like in various parts of the body, how they affect protein expression, as well as what they do when they cross a barrier or are excreted," said Witzmann.
"Studying the cellular alterations in the urine-blood barrier in the kidney caused by repeated exposure to low concentrations of CNPs is the initial step to understanding the assault on the human body of accidental exposure to CNPs but it is an important one," said Blazer-Yost.
Adam Amos, a study co-author, performed some of the initial work that contributed to this study during a five-semester intensive undergraduate research experience in the Blazer-Yost laboratory in the School of Science. He is currently attending the IU School of Medicine. This work was continued as part of the Ph.D. thesis research of Amiraj Banga.
In addition to Blazer-Yost, Witzmann, Amos and Banga, co-authors of "Effect of Carbon Nanoparticles on Renal Epithelial Cell Structure, Barrier Function, and Protein Expression" are Ellen Chernoff, Ph.D. of the School of Science at IUPUI; Xianyin Lai, Ph.D. of the IU School of Medicine and Cheng Li, Ph.D. and Somenath Mitra, Ph.D. of the New Jersey Institute of Technology. The School of Science and the IU School of Medicine are located on the IUPUI campus.
The study was funded by the National Institute of General Medical Sciences of the National Institutes of Health.
Carbon Cycle Reaches Earth's Lower Mantle: Evidence of Carbon Cycle Found in 'Superdeep' Diamonds From Brazil
September 19, 2011
The carbon cycle, upon which most living things depend, reaches much deeper into Earth than generally supposed -- all the way to the lower mantle, researchers report.
The findings, which are based on the chemistry of an unusual set of Brazilian diamonds, will be published online by the journal Science, at the Science Express Web site, on 15 September. Science is published by AAAS, the non-profit, international science society.
"This study shows the extent of Earth's carbon cycle on the scale of the entire planet, connecting the chemical and biological processes that occur on the surface and in the oceans to the far depths of Earth's interior," said Nick Wigginton, associate editor at Science.
"Results of this kind offer a broader perspective of planet Earth as an integrated, dynamic system," he said.
The carbon cycle generally refers to the movement of carbon through the atmosphere, oceans, and the crust. Previous observations suggested that the carbon cycle may even extend to the upper mantle, which extends roughly 400 kilometers into Earth. In this region, plates of ocean crust -- bearing a carbon-rich sediment layer -- sink beneath other tectonic plates and mix with the molten rock of the mantle.
Seismological and geochemical studies have suggested that oceanic crust can sink all the way to the lower mantle, more than 660 kilometers down. But actual rock samples with this history have been hard to come by.
Michael Walter of the University of Bristol and colleagues in Brazil and the United States analyzed a set of "superdeep" diamonds from the Juina kimberlite field in Brazil. Most diamonds excavated at Earth's surface originated at depths of less than 200 kilometers. Some parts of the world, however, have produced rare, superdeep diamonds, containing tiny inclusions of other material whose chemistry indicates that the diamonds formed at far greater depths.
The Juina-5 diamonds studied by Walter and colleagues contain inclusions whose bulk compositions span the range of minerals expected to form when basalt melts and crystallizes under the extreme high pressures and temperatures of the lower mantle.
Thus, these inclusions probably originated when diamond-forming fluids incorporated basaltic components from oceanic lithosphere that had descended into the lower mantle, the researchers have concluded.
If this hypothesis is correct, then the carbon from which the diamonds formed may have been deposited originally within ocean crust at the seafloor. A relative abundance of light carbon isotopes in the Juina-5 diamonds supports this idea, since this lighter form of carbon is found at the surface but not generally in the mantle, the authors say.
The diamond inclusions also include separate phases that appear to have "unmixed" from the homogenous pool of material. This unmixing likely happened as the diamonds traveled upward hundreds of kilometers into the upper mantle, the researchers say.
After the diamonds formed in the lower mantle, they may have been launched back near the surface by a rising mantle plume, Walter and colleagues propose.
This research was supported by the Natural Environment Research Council and the National Science Foundation.
Targeting Cholesterol to Fight Deadly Brain Cancers
September 19, 2011
Blocking the uptake of large amounts of cholesterol into brain cancer cells could provide a new strategy to battle glioblastoma, one of the most deadly malignancies, researchers at UCLA's Jonsson Comprehensive Cancer Center have found.
The study, done in cells lines, mouse models and analysis of tissue from brain cancer patients, uncovered a novel mechanism by which the most commonly activated oncogene, the mutated epidermal growth factor receptor (EGFR), overcomes normal cell regulatory mechanisms to feed large amounts of cholesterol to the brain cancer cells, said Dr. Paul Mischel, a professor of pathology and laboratory medicine and molecular and medical pharmacology, a Jonsson Cancer Center researcher and senior author of the study.
The study appears Sept. 15 in Cancer Discovery, the newest peer-reviewed journal of the American Association for Cancer Research. It shows that EGFRvIII, common in glioblastoma, promotes the import of cholesterol into cancer cells by up-regulating its cellular receptor, the LDL receptor, promoting rapid tumor growth and survival.
There are at least three ways by which cells normally tightly control their cholesterol levels -- synthesis, import and efflux, or pumping out the cholesterol, Mischel said.
"Our study found that the mutant EGFR hijacks this system, enabling cancer cells to import large amounts of cholesterol through the LDL receptor," Mischel said. "This study identifies the LDL receptor as a key regulator of cancer cell growth and survival, and as a potential drug target."
Mischel and his colleagues hypothesized that targeting the LDL receptor for destruction could result in strong anti-tumor activity against glioblastoma. They showed that a drug that activates the nuclear Liver X Receptor, a critical regulator of intracellular cholesterol that ensures appropriately balanced levels, degraded the LDL receptor in tumor cells bearing EGFR mutations, potently killing the cancerous tumors in mice.
About 45 percent of glioblastoma patients have cancers driven by mutated EGFR, so the findings have the potential to help almost half of those diagnosed with this aggressive malignancy. EGFR also is mutated in a number of other cancers, indicating that these findings may have relevance for other malignancies.
"This study suggests a potential therapeutic strategy to treat glioblastoma, and potentially a broader range of cancer types," Mischel said.
In a previous study, Mischel showed that inhibiting fatty acid synthesis in brain cancer cells may offer an additional option to treat those with mutated EGFR. Rapidly dividing cancer cells also require these fatty acids to form new membranes and provide energy for the cells. Mischel and his team found the same cell signaling pathway is at work in fatty acid synthesis and the import of cholesterol into cancer cells.
"That was a surprise here, this ghastly trick of the cancer cells," Mischel said. "The same mutation is coordinately regulating both the cholesterol and fatty acid synthesis mechanisms."
Going forward, Mischel and his colleagues will do more preclinical studies that could lead to clinical trials of drugs that activate the Liver X receptor.
Glioblastoma is the most common brain malignancy and one of the most lethal of all cancers, killing most of those diagnosed within 12 to 15 months despite aggressive treatment. It is also one of the most chemotherapy- and radiation-resistant cancers. New treatments are desperately needed, Mischel said.
"This study uncovers a novel and potentially therapeutically targetable tumor cell growth and survival pathway, which could result in more effective treatments for patients," he said.
Mischel's findings are the result of a collaboration with Dr. Peter Tontonoz, a Howard Hughes Medical Institute investigator and a professor of pathology and laboratory medicine at UCLA, Dr. Timothy Cloughesy, professor of neurology and director of neuro oncology at UCLA's Jonsson Comprehensive Cancer Center, and Dr. Deliang Guo, an assistant professor of radiation oncology at the Ohio State University Comprehensive Cancer Center.
The study was funded by the Rose DeGangi American Brain Tumor Association Translational Grant, the National Institutes of Health, the California Institute of Regenerative Medicine, Accelerate Brain Cancer Cure, STOP Cancer, John W. Carson Foundation and the Lya and Harrison Latter endowed chair.
The stars are boiling! This is because of the energy generated in the center of the star that wants to escape. If this does not happen quickly enough, the star starts to 'boil' in the outer layers causing vibrations that result in light variations, like in the Sun. Such oscillations have now been discovered by Victoria Antoci and collaborators using the NASA spacecraft Kepler, but in a much hotter star.
The scientists publish this in the most recent issue of Nature.
Besides the discovery of Earth-like planets, astronomy is concerned with research on stellar oscillations, among many other topics. The vibrations cause periodic brightness variations of some stars. Asteroseismology works just like the seismic exploration of Earth's interior: the frequencies of seismic waves depend on mass and composition of a body and therefore allow to tomographically reproduce its interior structure.
What causes stellar oscillations?
Several mechanisms maintain periodic oscillations in stars. In the Sun it is "seething" (convection) in the outer layers, comparable with boiling water and the consequent audible sound of the pot. In stars with masses some 1.5 times solar and more it is the so-called "kappa mechanism" that excites periodic pulsations. "This process works like a heat or Diesel engine" explains Victoria Antoci from the Institute of Astronomy at the University of Vienna.
Because of decades of research on solar oscillations it is known that the energy in the outer 30 per cent of the solar radius is transported by convection and below that, energy is transported by radiation.
In stars twice as massive, only one per cent of the envelope is convective. Also in this case, the energy generated in the core is transported by radiation. Stars with even higher mass should no longer possess a convective envelope. However, where exactly it disappears is unknown because of the extreme physical conditions in this domain.
One possibility to explore this is asteroseismology of so-called Delta Scuti stars. These stars are in the mass range where the convective envelope disappears. Delta Scuti stars show periodic light variations due to pulsations excited by the kappa mechanism. "Since more than ten years, scientists predicted that despite the small depth (one per cent) of the convective envelope of Delta Scuti stars convection should have sufficient energy to excite solar-like pulsations as well. Finally we succeeded to prove this," Victoria Antoci is pleased.
Kepler confirms the theory
In the framework of her PhD thesis the scientist examined hundreds of stars observed with NASA's Kepler space telescope for solar-like oscillations and made a detection: the Delta Scuti star called HD 187547 is the first representative of the group showing both types of oscillations. "With HD 187547 we found the ideal object to study different processes and their interaction under extreme physical conditions" says Gerald Handler from Nicolaus Copernicus Center in Warsaw, the advisor of Victoria Antoci's dissertation.
Statements about the actual depth of the outer convective layer are possible for the first time thanks to the work published in Nature, as is a calibration of convection models in this temperature domain. In addition, the presence of two different types of stellar oscillations permits to model the interior structure of HD 187547 with unprecedented precision. The scientists also determined that HD 187547 has unusual abundances of certain chemical elements on its surface, most probably a consequence of slow stellar rotation. Heavy elements dwindle down and become less abundant in the star's spectrum (only the stellar surface is directly observable). On the other hand, light elements are pushed upwards and appear more abundant. This physical process is known as diffusion and is not fully understood in stars such as HD 187547.
Biochemical Cell Signals Quantified: Data Capacity Much Lower Than Expected
September 19, 2011
Just as cell phones and computers transmit data through electronic networks, the cells of your body send and receive chemical messages through molecular pathways. The term "cell signaling" was coined more than 30 years ago to describe this process.
Now, for the first time, scientists have quantified the data capacity of a biochemical signaling pathway and found a surprise -- it's way lower than even an old-fashioned, dial-up modem.
"This key biochemical pathway is involved in complex functions but can transmit less than one bit -- the smallest unit of information in computing," says Ilya Nemenman, an associate professor of physics and biology at Emory University. "It's a simple result, but it changes our view of how cells access chemical data."
The journal Science is publishing the discovery by Nemenman and colleagues from Johns Hopkins University, including Andre Levchenko, Raymond Cheong, Alex Rhee and Chiaochun Joanne Wang.
During the 1980s, cell biologists began identifying key signaling pathways such as nuclear factor kappa B (NF-kB), known to control the expression of genes in response to everything from invading pathogens to cancer. But the amount of information carried by chemical messengers along these pathways has remained a mystery.
"Without quantifying the signal, using math and computer analysis to attach a number to how much information is getting transmitted, you have a drastically incomplete picture of what's going on," says Nemenman, a theoretical biophysicist.
He and Levchenko, a biomedical engineer, began discussing the problem back in 2007 after they met at a conference.
Levchenko developed microfluidic and measurement techniques to conduct experiments on bio-chemical signaling of the NF-kB pathway, and measure the transmissions occurring on the pathway in many thousands of cells at one time. Nemenman formulated the theoretical framework to analyze and quantify the results of the experiments.
"It was a shock to learn that the amount of information getting sent through this pathway is less than one bit, or binary digit," Nemenman says. "That's only enough information to make one binary decision, a simple yes or no."
And yet NF-kB is regulating all kinds of complex decisions made by cells, in response to stimuli ranging from stress, free radicals, bacterial and viral pathogens and more. "Our result showed that it would be impossible for cells to make these decisions based just on that pathway because they are not getting enough information," Nemenman says. "It would be like trying to send a movie that requires one megabit per second through an old-style modem that only transmits 28 kilobits per second."
They analyzed the signals of several other biochemical pathways besides NF-kB and got a similar result, suggesting that a data capacity of less than one bit could be common. So if cells are not getting all the information through signaling pathways, where is it coming from?
"We're proposing that cells somehow talk with each other outside of these known pathways," Nemenman says. "A single cell doesn't have enough information to consider all the variables and decide whether to repair some tissue. But when groups of cells talk to each other, and each one adds just a bit of knowledge, they can make a collective decision about what actions to take."
He compares it to a bunch of people at a cocktail party, with cell phones that have weak signals pressed to their ears. Each person is receiving simple messages via their phones that provide a tiny piece to a puzzle that needs to be solved. When the people chatter together and share their individual messages, they are able to collectively arrive at a reliable solution to the puzzle.
A similar phenomenon, called population coding, had been identified for the electrical activity of neural networks, but Nemenman and his colleagues are now applying the idea to bio-chemical pathways.
They hope to build on this research by zeroing in on the role of cell signaling in specific diseases.
In particular, Nemenman wants to analyze and compare the signaling capacities of a cancerous cell versus a normal cell.
"Cancerous cells divide when they shouldn't, which means they are making bad decisions," he says. "I would like to quantify that decision-making process and determine if cancer cells have reduced information transduction capacities, or if they have the same capacities as healthy cells and are simply making wrong decisions."
Nemenman uses a malfunctioning computer as an example. "If you push the 'a' key on your computer and a 'd' always shows up, that means the computer is misprogrammed but the information from your keystroke gets through just fine," he says. "But if you keep pressing the letter 'a' and different, random letters show up, that indicates a problem with the way the information is being transmitted."
That's the conclusion of a Dutch study published in Stroke: Journal of the American Heart Association in which researchers found that eating a lot of fruits and vegetables with white flesh may protect against stroke.
While previous studies have linked high consumption of fruits and vegetables with lower stroke risk, the researchers' prospective work is the first to examine associations of fruits and vegetable color groups with stroke.
The color of the edible portion of fruits and vegetables reflects the presence of beneficial phytochemicals such as carotenoids and flavonoids.
Researchers examined the link between fruits and vegetable color group consumption with 10-year stroke incidence in a population-based study of 20,069 adults, with an average age of 41. The participants were free of cardiovascular diseases at the start of the study and completed a 178-item food frequency questionnaire for the previous year.
Fruits and vegetables were classified in four color groups:
Green, including dark leafy vegetables, cabbages and lettuces
Orange/Yellow, which were mostly citrus fruits
Red/Purple, which were mostly red vegetables
White, of which 55 percent were apples and pears
During 10 years of follow-up, 233 strokes were documented. Green, orange/yellow and red/purple fruits and vegetables weren't related to stroke. However, the risk of stroke incidence was 52 percent lower for people with a high intake of white fruits and vegetables compared to people with a low intake.
Each 25 gram per day increase in white fruits and vegetable consumption was associated with a 9 percent lower risk of stroke. An average apple is 120 grams.
"To prevent stroke, it may be useful to consume considerable amounts of white fruits and vegetables," said Linda M. Oude Griep, M.Sc., lead author of the study and a postdoctoral fellow in human nutrition at Wageningen Uninversity in the Netherlands. "For example, eating one apple a day is an easy way to increase white fruits and vegetable intake.
"However, other fruits and vegetable color groups may protect against other chronic diseases. Therefore, it remains of importance to consume a lot of fruits and vegetables."
Apples and pears are high in dietary fiber and a flavonoid called quercetin. In the study, other foods in the white category were bananas, cauliflower, chicory and cucumber.
Potatoes were classified as a starch.
Previous research on the preventive health benefits of fruits and vegetables focused on the food's unique nutritional value and characteristics, such as the edible part of the plant, color, botanical family and its ability to provide antioxidants.
U.S. federal dietary guidelines include using color to assign nutritional value. The U.S. Preventive Health Services Taskforce recommends selecting each day vegetables from five subgroups: dark green, red/orange, legume, starchy and other vegetables.
Before the results are adopted into everyday practice, the findings should be confirmed through additional research, Oude Griep said. "It may be too early for physicians to advise patients to change their dietary habits based on these initial findings," she said.
An accompanying editorial notes that the finding should be interpreted with caution because food frequency questionnaires may not be reliable.
In addition, "the observed reduction in stroke risk might further be due to a generally healthier lifestyle of individuals consuming a diet rich in fruits and vegetables," writes Heike Wersching, M.D., M.Sc., of Institute of Epidemiology and Social Medicine at the University of Münster, in Germany.
Study co-authors are: W.M. Monique Verschuren, Ph.D.; Daan Kromhout, M.P.H., Ph.D.; Marga C. Ocké, Ph.D.; and Johanna M. Geleijnse, Ph.D. Author disclosures are on the manuscript.
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