Star Making Peaked Five Billion Years Ago; Expect Darkness
The universe reached the climax of its star-building activity five billion years ago—more recently than previously thought—according to researchers at Penn and the University of Edinburgh.
The astronomers sifted through the fossil record of 96,545 nearby galaxies to chronicle the complete history of star formation over time. Their findings, reported in the April 8 issue of the journal Nature, also determined that the more massive a galaxy the earlier its stars were formed, indicating that galaxies form stars differently depending on weight.
While paleontologists generally need to dig down to find their fossil record, Dr. Jimenez, assistant professor of physics and astronomy, and his colleagues needed only to look up, in this case to look up data from the Sloan Digital Sky Survey. To sift through data from nearly 100,000 galaxies, Dr. Jimenez and Edinburgh astronomer Alan Heavens created a program called Multiple Optimized Parameter Estimation and Data Compression (MOPED) that analyzes spectrum data quickly by compressing information into more manageable blocks.
"Stars of different masses evolve with different luminosities, so by looking at the integrated spectrum of a galaxy we can track those different luminosities, their masses and, therefore, how long ago they were born," Dr. Jimenez said.
According to the researchers' findings, star formation in the universe peaked, on average, about five billion years ago. By the time our own sun was born, about 4.7 billion years ago, almost half of the stellar mass in the universe since the big bang was already created. Star formation has drastically dropped off since then and, as new stars are not being created faster than old stars are dying, this will lead to the gradual dimming of the universe.
The findings also show a difference in star formation between low-mass and high-mass galaxies. Galaxies with a higher mass, our own Milky Way among them, formed most of their stars well before galaxies of a lower mass did.
Contributing astronomers also include graduate student Benjamin Panter, and Dr. James Dunlop of the Institute for Astronomy at the University of Edinburgh. Funding for this research was partly provided by the NSF.
New Therapeutic Approach for Sickle Cell Disease
Penn's School of Medicine researchers have identified an embryonic protein present in all humans that, when produced in mice, dramatically reduces symptoms of sickle cell disease. The discovery raises the possibility of new treatment options for sickle cell patients, say co-authors Dr. J. Eric Russell, assistant professor of medicine and pediatrics, and Zhenning He, research specialist, department of medicine. The research appears in the April issue of Nature Medicine.
Sickle cell disease is an inherited, red-blood-cell disorder in humans characterized by chronic anemia, episodes of severe pain, and premature death. It is caused by an error in one of the genes that produces hemoglobin, an iron-protein component contained within the red blood cells that carry oxygen to body tissues. The defective gene directs production of abnormal hemoglobin, resulting in deformed (sickle-shaped) red blood cells that block small blood vessels. This results in pain, stroke, heart attacks, kidney failure, and premature death in adults and children.
Although there is no cure for sickle cell disease, treatments are available, including administration of the anti-cancer drug hydroxyurea, blood transfusions, and bone marrow transplantation. Hydroxyurea is widely used to reactivate the production of gamma globin, which substitutes for the defective component of hemoglobin, called beta globin. Although this approach does not cure the disease, it frequently results in a lessening of symptoms.
Dr. Russell and Dr. He used a novel approach to modify alpha globin, the other major component of hemoglobin. This could help patients who have responded poorly to conventional hydroxyurea treatment or who are unable to tolerate its side effects. Conceivably, therapies resulting from this study could be combined with standard treatments to further reduce disease severity.
The researchers genetically engineered mice with sickle cell disease to produce zeta globin, the embryonic form of the human alpha chain of hemoglobin. Unlike mice with sickle cell disease, the genetically altered mice had normal blood counts and were no longer anemic. In addition, the life span of their red blood cells was extended almost five-fold to normal levels. Sickled cells did not appear in the blood of the mice and kidney function normalized.
"Our work demonstrates a novel therapeutic approach that reverses the disease process in mice with sickle cell disease," says Dr. Russell. "Clearly, there is much more work to be done before this approach can be tested in humans. Nevertheless, targeted reactivation of zeta globin, either alone or in combination with existing treatments, anticipates therapies in humans that are more flexible and potentially more effective than those that are currently available for this devastating condition."
The research was supported in part by grants from the NIH.
Newly Found Dinosaur of the Montana Coastline
Through the cycads and gingkoes of the floodplains, not far from the Sundance Sea, strode the 50-foot-long Suuwassea, a plant-eating dinosaur with a whip-like tail and an anomalous second hole in its skull destined to puzzle paleontologists in 150 million years. According to researchers at Penn, Suuwassea emilieae is a smaller relative of Diplodocus and Apatosaurus and is the first named sauropod dinosaur from the Jurassic of southern Montana. Their findings currently appear in the journal Acta Paleontologica Polonica.
"Suuwassea is the first unequivocal new sauropod from the Morrison Formation–a 150-million-year-old geological formation extending from New Mexico to Montana–in more than a century. It has a number of distinguishing features, but the most striking is this second hole in its skull, a feature we have never seen before in a North American dinosaur," said Dr. Peter Dodson, senior author and professor of anatomy at Penn's School of Veterinary Medicine and professor in the Department of Earth and Environmental Sciences. "While its Diplodocus relatives have a single hole on the top of the skull related to the nasal cavity, paleontologists have yet to come up with a plausible use for this second hole."
The name Suuwassea comes from the Native American Crow word meaning "ancient thunder" and also a nod to "thunder lizard," the original nickname of the dinosaur now known as Apatosaurus. Emilieae is a reference to the late Emilie deHellebranth, whose financial support funded the dinosaur's excavation.
At the time Suuwassea was alive, this part of the Morrison Formation was near the shoreline of a long but shallow arm of ocean water called the Sundance Sea. The coastal ecosystem has not been the typical environment for Morrison Formation dinosaurs, which have mostly been found in a more arid region farther south. The discovery of this new species could suggest that the fauna of this area differed from the rest of the Morrison Formation or that this region was something of a lush Jurassic vacation spot.
Nowadays, the region is much more arid, and much of Suuwassea's partial skeleton was found exposed on the surface, from years of wind and rain erosion. The partial skeleton, which was deposited randomly by river flooding before fossilization, held enough distinguishing characteristics that Dr. Dodson and his colleagues could easily classify it as a new species.
"The extra hole in the skull is still mystery; it has only been seen before in two dinosaurs from Africa and one from South America. It is interesting that the two African dinosaurs are exactly the same age as Suuwassea, and all three are also related to the much larger Diplodocus and Apatosaurus," said Jerry Harris, coauthor and graduate student researcher in the department of earth and environmental science.
Near the excavation site of the Suuwassea remains, members of the expedition chanced upon the partial skeleton of a new dinosaur predator, currently under study by Penn researchers.
Funding for this research was supported by Emilie deHellebranth; Penn's Research Foundation, School of Veterinary Medicine and Department of Animal Biology; and the Penn Paleobiology Fund.
Failure of DNA Repair Precedes Final Stage of Leukemia
Medical researchers at the Abramson Cancer Center of the University of Pennsylvania have discovered that the last stage of chronic myelogenous leukemia (CML), a deadly blood cancer, is preceded by the unique blocking action of a blood cell's normal cycle of DNA production and repair. The researchers linked the blocking action to a known oncogene, BCR/ABL, and suspect it to be the cause of blast crisis, the second and final stage of CML disease when the body no longer makes enough healthy white blood cells to fight off infection or prevent bleeding. Their findings appear in the March 23 edition of the journal Cancer Cell.
It can take up to a year for a patient to transition from the first phase of CML to blast crisis. In this deadly, blast crisis phase of CML, new white blood cells fail to mature into fully-functioning cells—and, instead, become myeloblasts in a state of arrested differentiation.
In order to block ATR and DNA repair, cancer researchers also found that the concentration of BCR/ABL moves into the nucleus of the cell— where DNA is produced—from its original concentration in the cell's cytoplasm. Further research is planned to determine if this movement of BCR/ABL is a trigger or effect of blast crisis.
Researchers were able to determine the workings of BCR/ABL by comparing the amounts of damaged to un-damaged DNA in a cell line when the oncogene was turned "on" and "off." DNA damage was linked to the protein ATR and measured using comet assays.
"If blocking DNA repair proves to be the cause of blast crisis, then we may be able to prevent CML from progressing to its final stage by interrupting the action of cancer gene BCR/ABL," said Dr. Martin Carroll, assistant professor of medicine. "Ultimately, this could lead to a long-term treatment for the disease that may also be applied to other progressive cancers."
Funding was provided from Penn's School of Medicine and the NCI.
Aklylating DNA Damage Stimulates Necrotic Cell Death
Researchers at the Leonard and Madlyn Abramson Family Cancer Research Institute at Penn have found a second way by which chemotherapeutic agents can kill cancer cells. The finding—which appeared in the June 1 edition of the journal Genes & Development—represents an important advance in understanding how and why some cancer cells die and others do not in response to existing chemotherapy. The results suggest the possibility that targeted therapies can be developed which will force cancer cells to die before they can grow into tumors.
"This finding shows, for the first time, that cancer cells are unusually sensitive to dying by necrosis, when their ability to metabolize glucose is blocked," said Dr. Craig Thompson, Principal Investigator of the study and Scientific Director of the Abramson Family Cancer Research Institute (AFCRI). "Up until now, research has focused on finding ways to program cancer cells to die through apoptosis—a very regulated, orderly form of cell death that does not trigger an immune response. Now, we know that cancer cells can be forced to die, suddenly, through necrosis. If we can harness this method, which does trigger an immune response, then, the door will be opened to a whole new and less toxic way to treat cancer."
The researchers found that the induced necrotic cell death was specific to proliferating cancer cells. The rapid energy depletion was triggered by activation of a DNA repair protein, called PARP. Its activation leads to an inhibition of the cancer cell's ability to break down glucose to produce the cellular fuel ATP, a process termed glycolysis. In contrast, non-proliferating or non-cancerous cells did not exhibit energy depletion, as they produce most of their ATP by metabolizing a mixture of fats, proteins, and carbohydrates in a process termed oxidative phosphorylation. This explains why necrotic cell death, induced by the chemotherapeutic agents, was specific to cancer cells and did not affect healthy, non-proliferating cells. When PARP activation was blocked, necrotic cell death failed to occur despite exposure to the chemotherapeutic agents. The new work suggests that drugs directly activating PARP might prove effective at treating cancer without many of the serious side effects of existing chemotherapy.
"Our next step is to try to safely manipulate necrotic cell death in cancerous tumors," said Dr. Wei-Xing Zong, study author and Post-Doctoral Fellow at the AFCRI. "Ultimately, the hope is that this could lead to new, safer targeted therapies to kill cancer cells before they turn into deadly tumors that can spread elsewhere in the body."
Funding for the study, was provided through research grants from the AFCRI, Cancer Research Institute (CRI), and the Leukemia and Lymphoma Society of America.
Protein Difference Between Humans and Primates
In an effort to find the remaining genes that govern myosin—the major contractile protein that makes up muscle tissue—researchers at the School of Medicine have made a discovery that may be central to answering key questions about human evolution.
Published in the March 25 issue of Nature, Penn researchers have found one small mutation that undermines an entire myosin gene. Their estimated dating for the appearance of this mutation places it at about 2.5 million years ago, just prior to a period of major evolutionary changes in the hominid fossil record. These include the beginning of larger brain size, so important in making us human. While the characterization of this mutation may better help understand such genetic diseases as muscular dystrophy, this finding has potentially wider implications for re-interpreting long-held notions about the appearance and early evolution of the genus Homo. Anthropologists have long debated how humans evolved from ancestors with larger jaw muscles and smaller brains. This newly discovered mutation seems responsible for the development of smaller jaw muscles in humans as compared to non-human primates. In a classic case of scientific sleuthing, Dr. Hansell Stedman, associate professor of surgery, Dr. Nancy Minugh-Purvis, Director of Advanced Gross Anatomy, Department of Cell and Developmental Biology, and colleagues took their discovery of a mutation that prevents the expression of a variety of myosin—designated MYH16 on chromosome 7—to its ultimate context: what makes humans different from other primates.
The study began with the discovery of an unexpected similarity between an "anonymous" piece of the human genome sequence and some previously studied genes known to power muscle contraction. The surprise came when a small, inactivating deletion was found in this sequence, perhaps explaining why the computer programs had previously passed by the area without recognizing it as a gene.
To determine whether the mutation was a rare form of an active gene and not a mistake introduced by the technical nature of the investigation, the team tested DNA samples from geographically disparate human populations. They found the gene-inactivating mutation in all modern humans sampled-natives of Africa, South America, Western Europe, Iceland, Japan, and Russia.
Additional studies showed that versions of this gene in non-human primates bear the imprint of a critically important function for the animal, which implies that the mutation afflicts all humans, in one sense of the word, with the same inherited muscle "disease."
To find out in which tissue the MYH16 gene is normally activated, the investigators examined a wide range of muscle types in the readily available macaque monkey and humans. In macaques, they found the MYH16 protein was only made in a group of related muscles in the head, those involved principally with chewing and biting. In humans, they found that messenger RNA, which translates the genetic code into workaday proteins, was still active in these muscles, but no protein was being made by virtue of the mutation.
By comparing a portion of the MYH16 gene sequence in humans to that in five other animals-quantifying the so-called molecular clock-the researchers calculated that the inactivating mutation appeared in a hominid ancestor about 2.4 million years ago, after the lineages leading to humans and chimpanzees diverged. Shortly thereafter, roughly 2 million years ago, the less muscled, larger brained skulls of the earliest known members of the genus Homo start to appear in the fossil record.
From this the investigators postulated that the first early hominids born with two copies of the mutated MYH16 gene would show many effects from this single mutation-most notably a reduction in size and contractile force of the jaw-closing muscles, some of which exert tremendous stress across and/or cause deposition of additional bone atop growth zones of the braincase. Aspects of the evolutionary trend of shrinking jaws and teeth, resulting in the lighter, more delicate structure found in humans today, roughly coincided with the increase in brain size characterizing the evolution of Homo over the past two million years.
The research was supported in part by grants from the NIH, Muscular Dystrophy Association, Association Française contre les Myopathies, Veterans Administration, and Genzyme Corporation.
Bacterial Protein Recycling Factor Possible Key to New Class of Antibiotics
Understanding the last step of protein synthesis—the basic process of translating DNA into its final protein product—just became more clear both literally and figuratively. This final phase, called recycling, is essential for the proper function of all cells. Using a three-dimensional cryo-electron microscope to directly observe protein structure, investigators at the School of Medicine and the State University of New York, Albany can now visualize the exact configuration of a molecule called ribosome recycling factor (RRF) in the common bacteria Escherichia coli. This image—reported in the June 15 issue of the Proceedings of the National Academy of Sciences—may help guide the design of new antibiotics aimed at inhibiting RRF-related steps of protein synthesis.
"Every living organism has to have this last step, the recycling of spent protein synthesis machinery for the next round of translation," says Dr. Akira Kaji, professor of microbiology at Penn. "Strangely, at this day and age, this most fundamental process remained vague until we launched our studies of RRF." Most antibiotics influencing protein synthesis act by stopping its molecular machinery. However, none as yet target the recycling step.
The ribosome is the structure within cells on which amino acids are strung together to make proteins with the aid of transfer RNA (tRNA) and messenger RNA (mRNA). RRF, in conjunction with elongation factor G (EF-G), moves along the ribosome removing mRNA and tRNA, readying it to make more proteins.
In an earlier paper by Dr. Kaji and colleagues from Sweden, the crystal structure of RRF showed that RRF mimics the L-shape and dimension of tRNA. Chemical probing by Dr. Kaji and colleagues at the University of California, Santa Cruz showed the approximate ribosomal binding site of RRF. In the current PNAS paper, direct observation of the RRF-ribosome structure revealed the exact ribosomal position of bound RRF. It further showed that part of the ribosome contorts by a significant amount —molecularly speaking—when RRF binds to it.
More precisely, the position of the key helices of the ribosomal small and large subunits that hold mRNA move inward, suggesting that this movement may be essential for the release of mRNA from the ribosome. In addition, the RRF binding sites are very close to where the two ribosomal subunits are held together, which explains an earlier observation that the disassembly reaction by RRF may be followed by dissociation of the two subunits.
His lab is currently identifying the ribosomal site to which RRF is moved from the currently identified position. "It is from this position where RRF performs the final and the most important act-release of mRNA," says Dr. Kaji. "The fourth step of protein synthesis within human cells is shrouded in complete mystery and nothing is known. This fundamental step must be elucidated before we can take advantage of the fact that the same step is catalyzed by RRF in bacteria."
Almanac, Vol. 51, No. 1, July 13, 2004
July 13, 2004
Volume 51 Number 1