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Weekend of November 14, 2008---------------------------------News Archive/Return to Today's News Alerts
Fatty Diet in Pregnancy Increases Apetite for Fat in Fetus
A study in rats shows that exposure to a high-fat diet during pregnancy produces permanent changes in the offspring’s brain that lead to overeating and obesity early in life, according to new research by Rockefeller University scientists. This surprising finding, reported in the November 12 issue of The Journal of Neuroscience, provides a key step toward understanding mechanisms of fetal programming involving the production of new brain cells that may help explain the increased prevalence of childhood obesity during the last 30 years.
“We’ve shown that short-term exposure to a high-fat diet in utero produces permanent neurons in the fetal brain that later increase the appetite for fat,” says senior author Sarah F. Leibowitz, who directs the Laboratory of Behavioral Neurobiology at Rockefeller. “This work provides the first evidence for a fetal program that links high levels of fats circulating in the mother’s blood during pregnancy to the overeating and increased weight gain of offspring after weaning.”
Research in adult animals by Leibowitz and others has shown that circulating triglycerides stimulate brain chemicals known as orexigenic peptides, which in turn spur the animals to eat more. Scientists also have shown that obese and diabetic mothers produce heavier children and that exposure to fat-rich foods early in life leads to obesity in adulthood. These studies suggested that food intake and body weight may be programmed during fetal development. But little was known about the mechanism underlying this programming.
Leibowitz and her colleagues have identified mechanisms in the brain that explain this programming. They compared the effects of feeding pregnant rats a high-fat diet for two weeks with feeding a balanced diet containing a moderate amount of fat. The researchers found that rat pups born to mothers who consumed the high-fat diet, even after the diet had been removed at birth, ate more, weighed more throughout life and began puberty earlier than those born to mothers who ate a balanced diet for the same two-week period. They also had higher levels of triglycerides in the blood both at birth and as adults and greater production of brain peptides that stimulate eating and weight gain.
The investigators then looked at the pups’ brain development during the last week of pregnancy. They examined the number and types of neurons being born and made a surprising discovery: The pups from the mothers fed high-fat diets had, in utero, a much larger number of neurons that produce the appetite-stimulating orexigenic peptides — and they kept them throughout their lives. During gestation, the mother’s fat-rich diet also stimulated the proliferation of neuronal precursor cells and their differentiation and migration to obesity-promoting centers in the brain. In rats born to mothers on a balanced diet, these neurons were much fewer in number and appeared much later after birth.
“We believe the high levels of triglycerides that the fetuses are exposed to during pregnancy cause the growth of the neurons earlier and much more than is normal,” says Leibowitz.
The researchers hypothesize that because the mother must prepare her embryos to survive on her diet, they need to be born with the brain mechanisms that allow them to eat and metabolize it.
Leibowitz believes similar mechanisms may be operating in humans.
“We’re programming our children to be fat,” she says. “I think it’s very clear that there’s vulnerability in the developing brain, and we’ve identified the site of this action where new neurons are being born. We now need to understand how the lipids affect these precursor cells that form these fat-sensitive neurons that live with us throughout life."
TRAP Analysis - New Way to Study Development and Disease
Like skilled assassins, many diseases seem to know exactly what types of cells to attack. While decimating one cadre of cells, diseases will inexplicably spare a seemingly identical group of neighbors. What makes cells vulnerable or not depends largely on the kinds and amounts of proteins they produce — their “translational profile,” in the lingo of molecular biology. For this reason, scientists have struggled to parse the subtle molecular differences among the hundreds of specialized cell types that are tangled together in tissues like the brain.
Now, in back-to-back papers in the November 14 issue of the journal Cell, researchers at The Rockefeller University report a breakthrough in cellular analysis that slashes through this Gordian knot. The scientists have developed a method to reveal translational profiles by isolating the genetic messages that govern protein production in different cell types. The new method, translating ribosome affinity purification (TRAP), uses genetically engineered mice to capture these messages as they pass through the protein production factories called ribosomes. Because the mice have been made to express a specially tagged ribosome in only one particular cell type, the TRAP method can identify all the genetic messages that give that cell type its unique identity, including, perhaps, its susceptibility to disease.
So TRAP solves a problem that has been a fundamental barrier to a deeper understanding of the brain and how neurological diseases attack it. But because the method can be used to distinguish any type of cell in any tissue in any organ — not just brain cells — it has applications for research into afflictions as varied as cancer metastases, coronary artery disease and diabetes. The work is a collaboration between the labs of Rockefeller professors Nathaniel Heintz and Paul Greengard as well as colleagues at Northwestern University and the Translational Genomics Research Institute (TGen).
“We’ve created a novel, generally applicable tool that can be used by a broad spectrum of the scientific community,” says Heintz, who is the James and Marilyn Simons Professor, head of the Laboratory of Molecular Biology and a Howard Hughes Medical Institute investigator. “I think it will rapidly spread into many of areas of biology.” Greengard, Vincent Astor Professor and head of the Laboratory of Molecular and Cellular Neuroscience, says about half of the research in his lab now employs the new technique to study the biochemical basis of Parkinson’s, Alzheimer’s and Huntington’s diseases, as well as the still-mysterious ways in which psychoactive drugs fight schizophrenia and depression. TRAP should fundamentally change biochemical studies of the brain and the speed at which they yield results, he says. “We can look at a thousand genes instead of one at a time, so things should clear a thousand times faster,” says Greengard, who won the Nobel Prize in Physiology or Medicine in 2000 for research into how neurons communicate.
The TRAP method grew out of a project known as GENSAT (for Genetic Expression Nervous System Atlas) that Heintz and Rockefeller professor Mary Beth Hatten launched in 2000 to visualize the contributions of individual genes to the mouse brain. Heintz and his colleagues had developed a technique to engineer large pieces of DNA carried in bacterial artificial chromosomes (BACs), which can insinuate themselves into the genomes of other organisms. They were able to insert the genetic code for green fluorescent protein (EGFP) within the regulatory domain of any gene of interest. When one of these modified BACs is transferred into mice, expression of the EGFP mimics that of the gene of interest, lighting up cells with a green glow that shows researchers all of the cells in which that particular gene functions.
The GENSAT database laid out in glowing green myriad cell types of the mouse brain. And it provided genetic markers for each kind. But it was an accomplishment that was also a taunt. Ultimately, the researchers wanted to go deeper to understand the precise biochemical characteristics of the cell types they had brought into focus, to learn what makes cells vulnerable to attack — and possibly how to protect them from it — by discovering what’s unique to the susceptible cells and the ones that are resistant. Enter TRAP.
Heintz, postdoctoral fellow Myriam Heiman and colleagues attached an EGFP to the surface of the ribosome and used it as a handle to pick out the cell’s protein factories and the genetic messages passing through them, called messenger RNAs (mRNAs). Using the GENSAT techniques and findings, they designed new mouse lines that made tagged ribosomes in each of four different cell types. Heiman and colleagues focused on the brain cells that respond to dopamine, an important neurotransmitter involved in muscle movement and emotion regulation, among other things. They used the handle they had made to pluck out the ribosomes and mRNAs from these brain cells and freeze them within minutes of dissection, preserving the “messages” largely as they were inside the living animal and minimizing degradation. Alternative approaches to getting the profiles of cell types in complex tissues have been disappointing because they require the physical isolation of whole cells from the tissues in which they are embedded. TRAP bypasses that logistical nightmare by going straight for the ribosome.
The method proved so sensitive that researchers were able to identify a few hundred genetic messages that differ between two types of dopamine-sensing brain cells that previously had seemed nearly identical. Because these cells are crucial elements of the neural circuit that degenerates in Parkinson’s and Huntington’s diseases, the newly identified proteins could aid in the design of drugs that would allow these two key cell types to be treated independently of one another.
“We can probe into each cell type, see what is there and possibly identify better therapeutic targets,” says Heiman. “This approach is much more in line with a rational drug design.”
In a major application of TRAP published as a separate study in the same issue of Cell, Rockefeller scientists led by research associate Joseph Doyle and postdoctoral associate Joseph Dougherty went on to characterize the protein profiles of 24 types of cells in the central nervous system, identifying thousands of proteins that were previously unassociated with known cell types. The work in Cell provides the research community with 16 lines of transgenic mice that can be used for a sweeping range of potential neurological experiments. Heintz says his lab will make many more as they pursue detailed studies of other cell types.
“We can now study the molecular phenotypes that occur in specific cell types in response to genetic, environmental or pharmacological perturbations, determine the precise changes within specific cell types as they progress through development and examine the detailed properties of cells as they succumb to the pathological events occurring in neurological diseases such as ataxia telangiectasia, autism and Rett syndrome,” says Heintz. “We are very excited by the opportunities this offers to us and our colleagues for investigation of these issues.”
Prehistoric Pelvis Offers New Clues to Human Development
Discovery of the most intact female pelvis of Homo erectus may cause scientists to reevaluate how early humans evolved to successfully birth larger-brained babies.
"This is the most complete female Homo erectus pelvis ever found from this time period," said Indiana University Bloomington paleoanthropologist Sileshi Semaw. "This discovery gives us more accurate information about the Homo erectus female pelvic inlet and therefore the size of their newborns."
Semaw is a research scientist at the Stone Age Institute and leader of the Gona Project in Ethiopia.
The discovery will be published in Science this week (Nov. 14) by Semaw, who discovered the fossil pelvis in Ethiopia with a group of six other scientists that includes IU Department of Geosciences graduate student Melanie Everett.
Reconstructing pelvis bone fragments from the 1.2 million-year-old adult female, Semaw and his co-workers determined the early ancestor's birth canal was more than 30 percent larger than earlier estimates based on a 1.5-million-year-old juvenile male pelvis found in Kenya. The new female fragments were discovered in the Gona Study Area in Afar, Ethiopia, in 2001 and excavation was completed in 2003.
Scientists also were intrigued by other unique attributes of the specimen, such as its shorter stature and broader body shape more likely seen in hominids adapted to temperate climates, rather than the tall and narrow body believed to have been efficient for endurance running.
Early humans became taller and narrower over time, scientists believe, partly due to long distance running and to help them maintain a constant body temperature. One consequence, however, is that a narrower pelvis would have been less accommodating to producing larger-brained offspring.
But rather than a tall, narrow hominid with the expected slight pelvic region, Semaw and the Gona researchers found evidence of a hominid ready to produce offspring with a much larger brain size.
"The female Homo erectus pelvic anatomy is basically unknown," Semaw said. "And as far as the fossil pelvis of ancestral hominids goes, all we've had is Lucy (dated at 3.2 million years and also found in Ethiopia), and she is very much farther back in time from modern humans."
Scientists studying early man predominantly find fragments of craniums and dental remains, while fossil bones from the neck down are rarely discovered. Even more difficult to verify are Homo erectus fossil bones that can be identified as those belonging to a female.
Scientists had thought early adult Homo erectus females, because of the assumed small birth canal, would produce offspring with only a limited neonatal brain size. These young would have then experienced rapid brain growth while still developmentally immature, leading researchers to envision a scenario of maternal involvement and child-rearing on par with that of modern humans. But those theories had been based upon extrapolations from the existing male skeleton from Kenya.
"This find will give us far more accurate information," Semaw said.
Semaw is also a research scientist at the Stone Age Institute, a research center near Bloomington dedicated to the study of early human evolution and culture. It is affiliated with Indiana University's CRAFT, the Center for Research into the Anthropological Foundations of Technology.
Gona has turned out to be a productive dig site for Semaw. In 1997 Semaw and colleagues reported the oldest known stone tools used by ancestral humans. Then in 2004 he coauthored a paper summarizing Gona's geological properties and the site's cornucopia of hominid fossils spanning several million years. At the time, Science gave the article an "Editor's Choice" recognition. In 2005 he and colleagues published an article in Nature announcing the discovery of Ardipithecus ramidus, one of the earliest ancestral hominids, dating between 4.3 and 4.5 million years ago.
Arsenic = Cardiovascular Disease at EPA Standards
When mice are exposed to arsenic at federally-approved levels for drinking water, pores in liver blood vessels close, potentially leading to cardiovascular disease, say University of Pittsburgh researchers in the Dec. 1 issue of the Journal of Clinical Investigation, available online Nov. 13. The study, while preliminary, also reveals how an enzyme linked to hypertension and atherosclerosis alters cells, and may call into question current Environmental Protection Agency standards that are based solely on risks for cancer.
In the study, Aaron Barchowsky, Ph.D., associate professor of environmental and occupational health at the University of Pittsburgh Graduate School of Public Health, and his research team looked at specialized cells in the liver called sinusoidal endothelial cells, which are tasked with removing wastes from blood and enabling nutrients to regulate metabolism. After exposing mice to 10 to 100 parts per billion (ppb) of arsenic over a two-week period, the cells were less able to remove damaged proteins from the blood and lost their characteristic pores or "windows," severely compromising the cells' ability to effectively exchange nutrients and waste. Dr. Barchowsky notes that despite their small size, mice are usually less sensitive to the effects of arsenic than people
The current EPA standard for arsenic in public water systems is 10 ppb, reduced from 50 ppb in 2006. The standard applies only to drinking water sources that serve more than 20 people.
"These results are important since this type of cellular dysfunction, over time, can impair the body's ability to clear fats and waste proteins that build up in blood vessels and can lead to cardiovascular diseases such as hypertension and atherosclerosis," said Dr. Barchowsky
According to Dr. Barchowsky, arsenic increased the activity of an enzyme called NADPH oxidase and the levels of oxidants it produces, compromising sinusoidal cell functions. Mice that lacked the enzyme did not have changes in liver blood vessels when exposed to arsenic and their cells were able to continue to function effectively.
"Our findings raise some concerns about whether current EPA-developed standards can effectively protect against cardiovascular risks posed by arsenic in drinking water," said Dr. Barchowsky. "We are especially concerned about water from individual wells in small, rural and semi-rural communities that are exempt from the EPA requirement and often contain levels of arsenic that exceed the EPA limit.
Next phases of the research will focus on further understanding how arsenic increases the production of oxidants by NADPH oxidase and determining effective preventative measures to lessen the impact of arsenic and other environmental exposures on the function of the endothelial cells. Additional studies will investigate the relationship between arsenic's effects on liver blood vessels and metabolism and disease-related changes in other blood vessels in the body.
Arsenic is a naturally occurring mineral primarily found in groundwater. Drinking high levels of arsenic over many years has been linked to increased risks for lung, bladder and skin cancers, as well as heart disease, diabetes and neurological damage.
THURSDAY, November 13, 2008---------------------------------News Archive/Return to Today's News Alerts
Newborn Neurons Can Go Wrong When Placed In Adult Brain
In a study that could have significant consequences for neural tissue transplantation strategies, researchers at the Salk Institute for Biological Studies report that inactivating a specific gene in adult neural stem cells makes nerve cells emerging from those precursors form connections in the wrong part of the adult brain.
In a paper published in the Nov. 11 issue of PLoS Biology, the team, led by Fred H. Gage, Ph.D., professor in the Laboratory of Genetics, discovered that a protein called cdk5 is necessary for both correct elaboration of highly branched and complex antennae, known as dendrites, which are extended by neurons, and the proper migration of cells bearing those antennae.
Previously described functions of cdk5 are manifold, among them neuronal migration and dendritic pathfinding of neurons born during embryonic development. "The surprising element was that the dendrites of newborn granule cells in the adult hippocampus lacking cdk5 stretched in the wrong direction and actually formed synapses with the wrong cells," explains Gage. Synapses are the specialized contact points where dendrites receive input from the long processes, or axons, of neighboring neurons.
These findings offer extremely valuable, although unanticipated, input for investigators whose goal is to develop transplantation strategies to treat brain injuries or neurodegeneration.
"Our data shows that cells that fail to find their 'right spot' might actually become integrated into the brain and possibly interfere with normal information processing," says the study's lead author Sebastian Jessberger, M.D., a former postdoc in the Gage lab and now an assistant professor at the Swiss Federal Institute of Technology in Zurich, Switzerland.
Gage agrees that this is a possibility, noting that therapeutic targeting of new tissue—which would presumably be derived from stem cells—to the brain or spinal cord may demand extreme accuracy. "Our findings reflect the need for therapeutic approaches that will assure that cells used in regenerative medicine are strategically placed so that they will make appropriate rather than promiscuous connections."
In the study investigators first injected retroviruses into part of the adult mouse brain known as the hippocampus, which is required for memory formation, to tag and knock out cdk5 activity in newborn granule cell neurons. Over time they observed that newborn neurons not only failed to move to their correct position in the brain but also sported stunted, mistargeted dendrites.
Jessberger explains that one might have predicted the opposite: that if immature neurons in the adult brain accidentally oriented their antennae in the wrong direction, they might fail to connect with cells in that network, or possibly even die. That they formed synaptic contact points was highly unanticipated. "We found that dendrites of cells lacking cdk5 seemed to integrate into the brain no matter what direction they grew in," he says.
In fact, the inappropriate synaptic connections made by cdk5-deficient cells persisted for months after the treatment with cdk5-antagonizing retroviruses. "One might have predicted that aberrant maturing nerve cells would get kicked out of the circuitry later on," reports Jessberger, who followed the behavior of newborn granule cells in treated mice long after cdk5 activity was eliminated. "Even after one year, some of those cells remained in the wrong part of the hippocampus."
The PLoS Biology paper is part of an extensive body of work contributed by the Gage lab to the field of adult neurogenesis. A decade ago Gage became one of the first investigators in the world to demonstrate the emergence of new neurons in brains of adult mammals, including humans. The current study specifically extends a 2005 PNAS study in which the lab searched the whole genome for chromosomal hot spots associated with adult neurogenesis.
That study, which was initiated by former postdoctoral fellow Gerd Kempermann, M.D, a co-author on the PLoS Biology paper and currently professor at the Center for Regenerative Therapies in Dresden (CRTD), had identified a large region of mouse chromosome 5 as an area of interest, and cdk5 was a gene embedded within that locus.
"The nice part of this story is that it emerged from a systems genetics approach," says Gage. "It continues our effort to apply genetic analysis to find chromosomal regions harboring genes that may play a critical role in neurogenesis."
Rheumatoid Arthritis Breakthrough
Rheumatoid arthritis is a painful, inflammatory type of arthritis that occurs when the body's immune system attacks itself. A new paper, published in this week's issue of PLoS Biology, reports a breakthrough in the understanding of how autoimmune responses can be controlled, offering a promising new strategy for therapy development for rheumatoid arthritis.
Normally, immune cells develop to recognise foreign material – antigens; including bacteria - so that they can activate a response against them. Immune cells that would respond to 'self' and therefore attack the body's own cells are usually destroyed during development. If any persist, they are held in check by special regulatory cells that provide a sort of autoimmune checkpoint. A key player in these regulatory cells is a molecule called Foxp3. People who lack or have mutated versions of the Foxp3 gene lack or have dysfunctional immune regulation, which causes dramatic autoimmune disease.
Scientists at the Medical Research Council's Laboratory of Molecular Biology in Cambridge, and funded by the Arthritis Research Campaign, have genetically engineered a drug-inducible form of Foxp3. Using this, scientists can 'switch' developing immune cells into regulatory cells that are then capable of suppressing the immune response.
Dr. Alexander Betz, Group Leader at the MRC laboratory, explains: "We have generated a modified form of Foxp3 which can be introduced into immune cells using genetic engineering techniques and then activated by a simple injection. When administered to and activated in animal models of arthritis, the modified cells inhibit or even reverse the disease process."
Further work is now aimed at elucidating the detailed molecular mechanisms involved in Foxp3 function, and transferring the experimental approach to human cells.
"First, we will develop a human Foxp3 factor and then assess its function in human arthritis models," said Dr Betz. "To be viable as a therapeutic option, the regulatory cells must fulfill certain criteria; they must be tissue matched to the patient for compatibility; they must only block the targeted disease and not the whole body immune response; and they have to home correctly to their target tissue. Establishing these criteria will be the key focus of our research.
"If Foxp3 functions as a key developmental switch in human immune cells, there is potential for a new avenue of therapy development that could transform arthritis treatment is substantial," he added.
A New Way to Study How Breast Cancer Spreads
In a breakthrough study appearing in advance online publication of Nature Methods, researchers at Albert Einstein College of Medicine of Yeshiva University describe for the first time a method of viewing individual breast cancer cells for several days at a time. The study, by scientists in Einstein's Gruss Lipper Biophotonics Center, provides detail on how cancer cells invade surrounding tissue and reach blood vessels. These movements are the first steps of the potentially deadly stage of cancer known as metastasis.
The new method of viewing cancer cells over several days in their natural environment is considered significant because prior methods of study only allowed cells to be viewed clearly for several hours at one time. Having a longer and clearer window into how cancer cells move during the early stages of metastasis may help scientists develop more effective cancer therapies. For 2007, the American Cancer Society reported that a woman with metastatic breast cancer had an average survival rate of two years.
Using intravital imaging, the researchers developed a "photoswitch"to mark cancer cells of their choosing within a tumor and observe how these tumor cells in mice move in their surrounding tissue. The technique allowed researchers to see individually labeled tumor cells move in real time and in living mice.
"One focus of our laboratories has been developing methods to see what cancer cells are doing when followed over time in the most realistic setting," said Jeffrey Segall, Ph.D., professor of anatomy and structural biology.
"Mapping the fate of tumor cells in different regions of a tumor was not possible before the development of the photoswitching technology," explained John Condeelis, Ph.D., co-chair and professor of anatomy and structural biology and co-director of the Gruss Lipper Biophotonics Center.
The new method involves the placement of a frame containing a small glass window onto the breast tumor of a mouse formed from cancerous cells that have a specific tag. Through the glass, individual breast tumor cells are targeted with a laser that 'marks' the cancer cells red. By viewing the cells through the window using a microscope, researchers can follow the cells as they spread. The mouse can move around and live normally with the glass plate and then be anesthetized briefly for observance under the microscope. The marked cancer cells are followed over a period of days until they lose their brightness.
Using this technique, investigators found that breast cancer cells closer to blood vessels were more aggressive and directed in their invasiveness than cancer cells farther from blood vessels. The cancer cells near blood vessels also appeared in the lung indicating that they are disseminated throughout the body.
As co-lead author, Bojana Gligorijevic Ph.D., explained, "Our work showed how important the microenvironment of a tumor is to the behavior of a cancer cell and the metastatic outcome of the tumor itself. We can now look at the early steps of metastasis in high resolution and specific regions of the tumor."
This finding marks the first time a direct link was shown between the presence of blood vessels and the invasive ability of a cancer cell, which strengthens the growing theory that blood supply is crucial to effective metastasis. It also suggests that many cancer therapies currently in development, which are directed at cutting off blood supply to tumors, may be on the right track.
The research was conducted by Dmitriy Kedrin, Bojana Gligorijevic, Ph.D. and team leader Jacco van Rheenen, Ph.D. under the direction of Drs. Segall and Condeelis. Vladislav Verkhusha, Ph.D., associate professor of anatomy and structural biology, and Jeffrey Wyckoff, M.F.A., B.S., senior associate of anatomy and structural biology, both members of the Biophotonics Center, contributed novel photo-switching protein, and expertise in intravital imaging, respectively. This study required this broad multidisciplinary team and the resources of the Center to make the technical leap needed to achieve this new result. The Center has been supported by the generous contributions of Evelyn Lipper.
Each year, cancer kills 553,000 people in the U.S. Most cancer deaths are caused by complications from metastasis, the spread of cancer cells to distant tissues and organs through the blood, rather than from the primary tumor itself. This research provides a powerful tool for studying cancer metastasis and is part of a growing body of Einstein cancer research that sheds light on how cancer spreads.
The study has been chosen for highlight at the 48th Annual Meeting of The American Society of Cell Biology in San Francisco on December 15, 2008, to be presented by Dr. Gligorijevic.
WEDNESDAY, November 12, 2008---------------------------------News Archive/Return to Today's News Alerts
Evolution's New Wrinkle: Proteins With Cruise Control
A team of Princeton University scientists has discovered that chains of proteins found in most living organisms act like adaptive machines, possessing the ability to control their own evolution.
The research, which appears to offer evidence of a hidden mechanism guiding the way biological organisms respond to the forces of natural selection, provides a new perspective on evolution, the scientists said. The researchers -- Raj Chakrabarti, Herschel Rabitz, Stacey Springs and George McLendon - made the discovery while carrying out experiments on proteins constituting the electron transport chain (ETC), a biochemical network essential for metabolism. A mathematical analysis of the experiments showed that the proteins themselves acted to correct any imbalance imposed on them through artificial mutations and restored the chain to working order.
"The discovery answers an age-old question that has puzzled biologists since the time of Darwin: How can organisms be so exquisitely complex, if evolution is completely random, operating like a 'blind watchmaker'?" said Chakrabarti, an associate research scholar in the Department of Chemistry at Princeton. "Our new theory extends Darwin's model, demonstrating how organisms can subtly direct aspects of their own evolution to create order out of randomness."
The work also confirms an idea first floated in an 1858 essay by Alfred Wallace, who along with Charles Darwin co-discovered the theory of evolution. Wallace had suspected that certain systems undergoing natural selection can adjust their evolutionary course in a manner "exactly like that of the centrifugal governor of the steam engine, which checks and corrects any irregularities almost before they become evident." In Wallace's time, the steam engine operating with a centrifugal governor was one of the only examples of what is now referred to as feedback control. Examples abound, however, in modern technology, including cruise control in autos and thermostats in homes and offices.
The research, published in a recent edition of Physical Review Letters, provides corroborating data, Rabitz said, for Wallace's idea. "What we have found is that certain kinds of biological structures exist that are able to steer the process of evolution toward improved fitness," said Rabitz, the Charles Phelps Smyth '16 Professor of Chemistry. "The data just jumps off the page and implies we all have this wonderful piece of machinery inside that's responding optimally to evolutionary pressure."
The authors sought to identify the underlying cause for this self-correcting behavior in the observed protein chains. Standard evolutionary theory offered no clues. Applying the concepts of control theory, a body of knowledge that deals with the behavior of dynamical systems, the researchers concluded that this self-correcting behavior could only be possible if, during the early stages of evolution, the proteins had developed a self-regulating mechanism, analogous to a car's cruise control or a home's thermostat, allowing them to fine-tune and control their subsequent evolution. The scientists are working on formulating a new general theory based on this finding they are calling "evolutionary control."
The work is likely to provoke a considerable amount of thinking, according to Charles Smith, a historian of science at Western Kentucky University. "Systems thinking in evolutionary studies perhaps began with Alfred Wallace's likening of the action of natural selection to the governor on a steam engine --- that is, as a mechanism for removing the unfit and thereby keeping populations 'up to snuff' as environmental actors," Smith said. "Wallace never really came to grips with the positive feedback part of the cycle, however, and it is instructive that through optimal control theory Chakrabarti et al. can now suggest a coupling of causalities at the molecular level that extends Wallace's systems-oriented approach to this arena."
Evolution, the central theory of modern biology, is regarded as a gradual change in the genetic makeup of a population over time. It is a continuing process of change, forced by what Wallace and Darwin, his more famous colleague, called "natural selection." In this process, species evolve because of random mutations and selection by environmental stresses. Unlike Darwin, Wallace conjectured that species themselves may develop the capacity to respond optimally to evolutionary stresses. Until this work, evidence for the conjecture was lacking.
The experiments, conducted in Princeton's Frick Laboratory, focused on a complex of proteins located in the mitochondria, the powerhouses of the cell. A chain of proteins, forming a type of bucket brigade, ferries high-energy electrons across the mitrochondrial membrane. This metabolic process creates ATP, the energy currency of life.
Various researchers working over the past decade, including some at Princeton like George McClendon, now at Duke University, and Stacey Springs, now at the Massachusetts Institute of Technology, fleshed out the workings of these proteins, finding that they were often turned on to the "maximum" position, operating at full tilt, or at the lowest possible energy level.
Chakrabarti and Rabitz analyzed these observations of the proteins' behavior from a mathematical standpoint, concluding that it would be statistically impossible for this self-correcting behavior to be random, and demonstrating that the observed result is precisely that predicted by the equations of control theory. By operating only at extremes, referred to in control theory as "bang-bang extremization," the proteins were exhibiting behavior consistent with a system managing itself optimally under evolution.
"In this paper, we present what is ostensibly the first quantitative experimental evidence, since Wallace's original proposal, that nature employs evolutionary control strategies to maximize the fitness of biological networks," Chakrabarti said. "Control theory offers a direct explanation for an otherwise perplexing observation and indicates that evolution is operating according to principles that every engineer knows."
The scientists do not know how the cellular machinery guiding this process may have originated, but they emphatically said it does not buttress the case for intelligent design, a controversial notion that posits the existence of a creator responsible for complexity in nature.
Chakrabarti said that one of the aims of modern evolutionary theory is to identify principles of self-organization that can accelerate the generation of complex biological structures. "Such principles are fully consistent with the principles of natural selection. Biological change is always driven by random mutation and selection, but at certain pivotal junctures in evolutionary history, such random processes can create structures capable of steering subsequent evolution toward greater sophistication and complexity." The researchers are continuing their analysis, looking for parallel situations in other biological systems.
Purdue Researcher Invents Molecule that Stops SARS
A Purdue University researcher has created a compound that prevents replication of the virus that causes SARS and could lead to a treatment for the disease.
"The outbreak of SARS in 2003 led to hundreds of deaths and thousands of illnesses, and there is currently no treatment," said Arun Ghosh, the Purdue professor that led the molecular design team. "Although it is not currently a threat, there is the concern that SARS could return or be used as a biological weapon. It is important to develop a treatment as a safeguard." According to the Centers for Disease Control and Prevention, the virus can be transmitted through coughing or sneezing, and the infection can quickly spread from person to person. SARS, or Severe Acute Respiratory Syndrome, spread through two dozen countries over a period of a few months before it was contained. A total of 8,098 people worldwide became ill and 774 died.
In addition to its ability to block the SARS virus, the molecular compound that inhibits the virus provides new insights into a group of proteins found in a range of diseases including childhood croup, herpes and cancer, Ghosh said. "The molecular inhibitor we developed is very potent against the SARS virus by binding to and blocking the use of a specific protein, called papain-like protease, or PLpro, involved in viral replication and evasion of the immune system," said Ghosh who has a joint appointment in chemistry and medicinal chemistry and molecular pharmacology. "This is the first design and discovery of an inhibitor for this class of proteins. We are hopeful that this will open the door to new treatments for other diseases as well."
Ghosh's group teamed with a research group led by Andrew Mesecar at the University of Illinois at Chicago. The National Institutes of Health infectious disease biodefense program selected the team and funded the research that has been published in the online version of the journal Proceedings of the National Academy of Sciences.
Mesecar's team screened more than 50,000 chemical compounds for the necessary properties to both block the virus and have the potential to become viable drug treatments. "Only two of the compounds we tested were identified as having the properties researchers believed could become drugs," said Mesecar, a professor of medicinal chemistry and pharmacognosy. "Using those two compounds, Arun Ghosh and his team increased the potency by almost two orders of magnitude."
Ghosh, who invented the HIV drug darunavir that entered the market in 2007, specializes in improving the treatment properties of molecular inhibitors through structure-based design. "The design of this inhibitor was a challenge because we did not know the structure of the compound, which shows us how an inhibitor works and what parts need to be amplified or changed," Ghosh said.
Kiira Ratia, a graduate student at the University of Illinois, provided a breakthrough when she captured the X-ray structure of the inhibitor molecule bound to the protein. The structure confirmed that the inhibitor would be a good candidate for drug development because it showed that the inhibitor did not bond too strongly to the protein, Ghosh said. "This was the first time the structure was revealed and we could see that the inhibitor filled the active site of the protein without using strong covalent bonds," he said. "This is very important for development of a therapeutic treatment because it means there is less of a chance for adverse side effects or toxicity, and the treatment can be easily reversed."
Often a protein involved in the disease process also plays a role in regular human biological processes. A safe and effective treatment needs to block enough of the protein to cripple the disease while not completely eliminating the protein from a person's system. It also must work through interactions that are easily reversed by ending treatment, he said.
The inhibitor has only been tested in the laboratory. It must be developed into a drug treatment and evaluated by the U.S. Food and Drug Administration before it could be used by patients, Ghosh said. In addition to Ghosh and Mesecar, co-authors of the paper detailing this work include, Ratia, Scott Pegan, Wentao Fu, Michael E. Johnson, Melissa Coughlin and Bellur S. Prabhakar from the University of Illinois; Jun Takayama from Purdue University; and Katrina Sleeman and Srendranath Baliji from Loyola University Chicago Stritch School of Medicine.
The team is evaluating the potential to design similar inhibitors for cancer and continues to work with the SARS inhibitor to create even more effective compounds.
Monkey Teeth Stem Cells Stimulate Growth of Brain Cells
Researchers at the Yerkes National Primate Research Center, Emory University, have discovered dental pulp stem cells can stimulate growth and generation of several types of neural cells. Findings from this study, available in the October issue of the journal Stem Cells, suggest dental pulp stem cells show promise for use in cell therapy and regenerative medicine, particularly therapies associated with the central nervous system.
Dental stem cells are adult stem cells, one of the two major divisions of stem cell research. Adult stem cells have the ability to regenerate many different types of cells, promising great therapeutic potential, especially for diseases such as Huntington’s and Parkinson’s. Already, dental pulp stem cells have been used for regeneration of dental and craniofacial cells.
Yerkes researcher Anthony Chan, DVM, PhD, and his team of researchers placed dental pulp stem cells from the tooth of a rhesus macaque into the hippocampal areas of mice. The dental pulp stem cells stimulated growth of new neural cells, and many of these formed neurons.
“By showing dental pulp stem cells are capable of stimulating growth of neurons, our study demonstrates the specific therapeutic potential of dental pulp stem cells and the broader potential for adult stem cells,” says Chan, who also is assistant professor of human genetics in Emory School of Medicine.
Because dental pulp stem cells can be isolated from anyone at any age during a visit to the dentist, Chan is interested in the possibility of dental pulp stem cell banking. “Being able to use your own stem cells for therapy would greatly decrease the risk of cell rejection that we now experience in transplant medicine,” says Chan.
Chan and his research team next plan to determine if dental pulp stem cells from monkeys with Huntington’s disease can enhance brain cell development in the same way dental pulp stem cells from healthy monkeys do.
For more than seven decades, the Yerkes National Primate Research Center, Emory University, has been dedicated to conducting essential basic science and translational research to advance scientific understanding and to improve the health and well-being of humans and nonhuman primates. Today, the center, as one of only eight National Institutes of Health–funded national primate research centers, provides leadership, training and resources to foster scientific creativity, collaboration and discoveries. Yerkes-based research is grounded in scientific integrity, expert knowledge, respect for colleagues, an open exchange of ideas and compassionate, quality animal care.
Within the fields of microbiology and immunology, neuroscience, psychobiology and sensory-motor systems, the center’s research programs are seeking ways to: develop vaccines for infectious and noninfectious diseases, such as AIDS and Alzheimer’s disease; treat cocaine addiction; interpret brain activity through imaging; increase understanding of progressive illnesses such as Parkinson’s and Alzheimer’s; unlock the secrets of memory; determine behavioral effects of hormone replacement therapy; address vision disorders; and advance knowledge about the evolutionary links between biology and behavior.
TUESDAY, November 11, 2008---------------------------------News Archive/Return to Today's News Alerts
How Cells Take Out the Trash to Prevent Disease
Garbage collectors are important for removing trash; without them waste accumulates and can quickly become a health hazard. Similarly, individual cells that make up such biological organisms as humans also have sophisticated methods for managing waste.
TFor example, cells have developed complex systems for recycling, reusing and disposing of damaged, nonfunctional waste proteins. When such systems malfunction and these proteins accumulate, they can become toxic, resulting in many diseases, including Alzheimer's, cystic fibrosis and developmental disorders.
Scott Emr, director of the Weill Institute for Cell and Molecular Biology at Cornell, and colleagues, describe in detail how cells recycle protein waste in two recent papers appearing in the journals Cell and Developmental Cell.
"We are interested in understanding how cells deal with garbage," said Emr. "It's really a very sophisticated recycling system."
Cells use enzymes known as proteases to break down proteins into their component amino acids in the cytoplasm -- the fluid inside the cell's surface membrane. Those amino acids are then reused to make new proteins. But water-insoluble proteins embedded in the cell's membrane require a much more complicated recycling process.
Emr's paper in Cell identifies a family of proteins that controls the removal of unwanted water-insoluble proteins from the membrane. The research advances understanding of how cells recognize which proteins out of hundreds on a cell's surface should be removed. For example, hormone receptors at a cell's surface signal such processes within the cell as growth and proliferation. To inactivate these receptors and terminate the growth signal, receptors are tagged for removal. Failure to inactivate can lead to developmental diseases and cancer.
The researchers, including postdoctoral fellows Jason MacGurn and Chris Stefan, identified nine related proteins in yeast, which they named the "arrestin-related trafficking" adaptors or ARTs. Each of these proteins identifies and binds to a different set of membrane proteins. Once bound, the ART protein links to an enzyme that attaches a chemical tag for that protein's removal. The ARTs are found in both yeast and humans, suggesting the fundamental nature of their function.
Once the protein is tagged, the piece of membrane with the targeted protein forms a packet, called a vesicle, that enters the cell's cytoplasm. There, the vesicle enters a larger membrane body called an endosome, which in turn dumps it into another compartment called the lysosome, where special enzymes break apart big molecules to their core units: proteins to amino acids, membranes to fatty acids, carbohydrates to sugars and nucleic acids to nucleotides, and those basic materials are then reused.
The paper in Developmental Cell, co-authored by Emr with postdoctoral fellows David Teis and Suraj Saksena, describes for the first time how a set of four proteins assemble into a highly ordered complex. This complex encircles membrane proteins that must be disposed of in the lysosome. Emr's lab was the first to identify and characterize these protein complexes (known as ESCRTs). The Developmental Cell paper describes the order of events in which the ESCRT complexes encircle and deliver "waste" proteins into vesicles destined for recycling in the lysosome.
Emr's ESCRT discovery has allowed researchers to better understand how the AIDS virus is released from its host cell. HIV hijacks the cell's ESCRT machinery during virus budding. "So, if you block the function of ESCRTs, you could block HIV release," said Emr.
Signaling Guides Cell Migration
The mysterious process that orchestrates cells to move in unison to form human and animal embryos, heal wounds, and even spread cancer depends on interaction between two well-known genetic signaling pathways, two University of Utah medical school researchers have discovered.
The study by Tatjana Piotrowski, Ph.D., assistant professor of neurobiology and anatomy, and doctoral student Andy Aman sheds new light on how the migration of groups of cells is coordinated and is the first to show a functional link between the Wnt and Fgf growth factor signaling pathways in a live animal model (zebrafish). The findings may give clues to how cancer metastasizes or spreads when cancerous cells move to different areas of the body.
Cell migration, though central to the development and maintenance of multicellular organisms, is not well understood, particularly in vivo or in live models. Researchers already knew the Wnt pathway has a role in embryogenesis and cancer by regulating cell-to-cell communication and that the Fgf pathway influences embryogenesis, wound healing, and cell proliferation. But Piotrowski's and Aman's study, published in the Nov. 11 issue of Developmental Cell, is the first to demonstrate that interaction between the two pathways is critical for proper collective cell migration.
"We looked at the question of how cells in the tip and the tail of a group of migrating cells communicate so that they move in a coordinated fashion," said Piotrowski, the paper's senior author.
To identify which genes are involved in collective cell migration, Piotrowski and Aman studied a group of migrating cells, called the lateral line primordium. During development the lateral line primordium migrates from the zebrafish head to the tail tip, periodically depositing sensory organs. The lateral line sensory system helps zebrafish and other aquatic vertebrates sense water movement.
Aman and Piotrowski discovered that both Wnt and Fgf pathway genes are activated.
But for proper migration, a cellular division of labor must take place: the Wnt pathway must be restricted to the primordium's tip and the Fgf pathway must be confined to the tail. If the Wnt pathway is not restricted to cells in the tip, a cellular receptor that normally senses guidance cues is turned off and primordium cells stall and tumble randomly instead of migrating directionally, according to the researchers.
To accomplish this division of labor, each pathway stimulates the production of molecular inhibitors that restrict Wnt and Fgf pathway signaling to the tip and tail, respectively. When the Fgf pathway is activated, inhibitors are produced that restrict Wnt pathway signaling to the primordium tip. Conversely, when the Wnt pathway is activated, inhibitors are produced that restrict the Fgf pathway to the tail, the researchers reported.
"Cells use many diverse molecules to communicate with one another and coordinate their behaviors," Piotrowski said. "This work makes a significant contribution to our understanding of how these diverse signaling molecules interact in intact animals and may provide insights into how defects in these interactions might lead to the progression of human disease."
While understanding the signaling between the Wnt and Fgf pathways can inform researchers about cell migration during development or in the adult, it also has the potential to help them learn more about how some types of cancer spread, according to Piotrowski.
Breast and prostate cancer both invade tissue in groups of cells, for example, and several studies by other researchers indicate groups of cancer cells, like the zebrafish primordium, might be separated into compartments by the Wnt and Fgf pathways. Interestingly, a gene mutation found in 80 percent of colon cancer cases causes Wnt pathway activation in too many cells, raising the question whether defective cell migration is a cause in tumor development.
Thus, by learning more about how cells migrate during normal development, researchers can gain insight into the molecular mechanisms that contribute to metastasis and tumor development of breast and colon cancer.
"The same genes involved in lateral line cell migration can cause aberrant migration in cancer cells," Piotrowski said. "By understanding how lateral line cells migrate, we possibly can understand which genes are not properly regulated when cancer spreads."
Uncovering Genetic Basis for Some Birth Defects
A multidisciplinary research team at Case Western Reserve University led by Gary Landreth, Ph.D., a professor in the School of Medicine's Department of Neurosciences, has uncovered a common genetic pathway for a number of birth defects that affect the development of the heart and head. Abnormal development of the jaw, palate, brain and heart are relatively common congenital defects and frequently arise due to genetic errors that affect a key developmental pathway.
The research, titled "Mouse and human phenotypes indicate a critical conserved role for ERK2 signaling in neural crest development" is published in the November 10 issue of the Proceedings of the National Academy of Sciences of the United States of America.
Landreth, also the senior author of the study, developed a mouse model of these disorders by removing a gene central to this developmental pathway, called ERK2. He, together with Dr. William Snider at the University of North Carolina, discovered that the mice missing the gene for ERK2 in neural crest cells had developmental defects resembling those of human patients with a deletion that includes this gene. The patients have features that are similar to DiGeorge syndrome, which is associated with cardiac and palate defects. Interestingly, the ERK2 gene is central to a well-known pathway already associated with a different distinct group of cardiac and craniofacial syndromes that include Noonan, Costello, Cardiofaciocutaneous syndrome, and LEOPARD syndrome.
Landreth enlisted the help of Michiko Watanabe, Ph.D., professor of Pediatrics at Case Western Reserve University School of Medicine to look at the mouse hearts. She and her team found that they had characteristic heart defects resembling those seen in the patients with ERK2 deletions. "Given Dr. Watanabe's findings, we determined that we had in fact developed animal models that mimicked the human deletion syndrome," said Landreth. "This work sheds light on how these developmental errors occur."
Remarkably, Dr. Sulagna Saitta, a human geneticist at Children's Hospital of Philadelphia had identified children who had comparable heart defects as well as subtle facial differences. These children were all missing a very small region of chromosome 22 that contained the ERK2 gene. Saitta agreed that the similarity in the anatomic structures affected in the mice and those in the patients who have lost one copy of this gene suggest that ERK2 and its pathway members are essential for normal development and might lead to these birth defects. These findings link together several distinct syndromes that are each characterized by cardiac and craniofacial abnormalities and show that they can result from perturbations of the ERK cascade.
Landreth and his team will take these findings back to the lab and find out exactly why cells need ERK2 during embryogenesis.
Without Enzymes, Biological Reaction Takes 2.3 Billion Years
All biological reactions within human cells depend on enzymes. Their power as catalysts enables biological reactions to occur usually in milliseconds. But how slowly would these reactions proceed spontaneously, in the absence of enzymes - minutes, hours, days? And why even pose the question?
One scientist who studies these issues is Richard Wolfenden, Ph.D., Alumni Distinguished Professor Biochemistry and Biophysics and Chemistry at the University of North Carolina at Chapel Hill. Wolfenden holds posts in both the School of Medicine and in the College of Arts and Sciences and is a member of the National Academy of Sciences. In 1995, Wolfenden reported that without a particular enzyme, a biological transformation he deemed "absolutely essential" in creating the building blocks of DNA and RNA would take 78 million years. "Now we've found a reaction that - again, in the absence of an enzyme - is almost 30 times slower than that," Wolfenden said. "Its half-life - the time it takes for half the substance to be consumed - is 2.3 billion years, about half the age of the Earth. Enzymes can make that reaction happen in milliseconds."
With co-author Charles A. Lewis, Ph.D., a postdoctoral scientist in his lab, Wolfenden published a report of their new findings recently in the online early edition of the Proceedings of the National Academy of Sciences. The study is also due to appear in the Nov. 11 print edition. The reaction in question is essential for the biosynthesis of hemoglobin and chlorophyll, Wolfenden noted. But when catalyzed by the enzyme uroporphyrinogen decarboxylase, the rate of chlorophyll and hemoglobin production in cells "is increased by a staggering factor, one that's equivalent to the difference between the diameter of a bacterial cell and the distance from the Earth to the sun."
"This enzyme is essential for both plant and animal life on the planet," Wolfenden said. "What we're defining here is what evolution had to overcome, that the enzyme is surmounting a tremendous obstacle, a reaction half-life of 2.3 billion years." Knowing how long reactions would take without enzymes allows biologists to appreciate their evolution as prolific catalysts, Wolfenden said. It also enables scientists to compare enzymes with artificial catalysts produced in the laboratory.
"Without catalysts, there would be no life at all, from microbes to humans," he said. "It makes you wonder how natural selection operated in such a way as to produce a protein that got off the ground as a primitive catalyst for such an extraordinarily slow reaction." Experimental methods for observing very slow reactions can also generate important information for rational drug design based on cellular molecular studies. "Enzymes that do a prodigious job of catalysis are, hands-down, the most sensitive targets for drug development," Wolfenden said. "The enzymes we study are fascinating because they exceed all other known enzymes in their power as catalysts."
Wolfenden has carried out extensive research on enzyme mechanisms and water affinities of biological compound. His work has also influenced rational drug design, and findings from his laboratory helped spur development of ACE inhibitor drugs, now widely used to treat hypertension and stroke. Research on enzymes as proficient catalysts also led to the design of protease inhibitors that are used to treat HIV infection. "We've only begun to understand how to speed up reactions with chemical catalysts, and no one has even come within shouting distance of producing, or predicting the magnitude of, their catalytic power," Wolfenden said.
MONDAY, November 10, 2008---------------------------------News Archive/Return to Today's News Alerts
Bionic Assassins See Through HIV's Many Disguises
HIV is a master of disguise, able to rapidly change its identity and hide undetected in infected cells. But now, in a long-standing collaborative research effort partially-funded by the Wellcome Trust, scientists have engineered immune cells to act as ‘bionic assassins’ that see through HIV’s many disguises.
The findings of the study, published online today in the journal 'Nature Medicine', may have important implications for developing new treatments for HIV and slowing - or even preventing - the onset of AIDS. Over 33 million people were estimated to be living with HIV worldwide in 2007. Although antiretroviral drugs have been successful in delaying the onset of AIDS for several years, the drugs are expensive, have serious side effects and must be taken for life. No vaccine or cure yet exists and drug resistance is increasingly becoming a problem.
When viruses enter our bodies, they hijack the machinery of host cells in order to replicate and spread infection. When our body’s cells are infected with a virus they expose small parts of the virus on their surface, offering a "molecular fingerprint" called an epitope for killer T cells from the immune system to identify. This triggers an immune response, eliminating the virus and any cells involved in its production.
As with other viruses, HIV enters the body and replicates itself rapidly. However, it also has the ability to mutate quickly, swiftly disguising its fingerprints to allow it to hide from killer T cells.
"When the body mounts a new killer T-cell response to HIV, the virus can alter the molecular fingerprint that these cells are searching for in just a few days," explains Professor Andy Sewell from Cardiff University, co-lead author of the study. "It’s impossible to track and destroy something that can disguise itself so readily. As soon as we saw over a decade ago how quickly the virus can evade the immune system we knew there would never be a conventional vaccine for HIV."
Now, Professor Sewell and colleagues from Adaptimmune Ltd and the University of Pennsylvania School of Medicine have engineered and tested a killer T-cell receptor that is able to recognise all of the different disguises that HIV is known to have used to evade detection. The researchers attached this receptor to the killer T cells to create genetically engineered 'bionic assassins' able to destroy HIV-infected cells in culture.
"The T-cell receptor is nature’s way of scanning and removing infected cells - it is uniquely designed for the job but probably fails in HIV because of the tremendous capability of the virus to mutate," says Dr Bent Jakobsen, co-lead author and Chief Scientific Officer at Adaptimmune Ltd, the company which owns the technology. "Now we have managed to engineer a receptor that is able to detect HIV’s key fingerprints and is able to clear HIV infection in the laboratory. If we can translate those results in the clinic, we could at last have a very powerful therapy on our hands."
The researchers believe that HIV's chameleon-like ability may still prevent the virus from being completely flushed out of the body. It could mutate and change its fingerprint further, hiding behind these new disguises and evading detection. However, each time the virus is forced to mutate to avoid detection by killer T cells, it appears to become less powerful.
"In the face of our engineered assassin cells, the virus will either die or be forced to change its disguises again, weakening itself along the way," says Professor Sewell. "We’d prefer the first option but I suspect we’ll see the latter. Even if we do only cripple the virus, this will still be a good outcome as it is likely to become a much slower target and be easier to pick off. Forcing the virus to a weaker state would likely reduce its capacity to transmit within the population and may help slow or even prevent the onset of AIDS in individuals."
Pending regulatory approval, Professor Carl June and Dr James Riley from the University of Pennsylvania in Philadelphia will shortly begin clinical trials using the engineered killer T cells.
"We hope to begin testing the treatment on patients with advanced HIV infection next year," says Professor June. "If the therapy in that group proves successful, we will treat patients with early stage well-controlled HIV infection. The goal of these studies is to establish whether the engineered killer T cells are safe, and to identify a range of doses of the cells that can be safely administered."
"The AIDS virus evades human immunity in all it infects," says Professor Rodney Phillips from the University of Oxford, where the collaborative research effort first began in 2003. "Until now no one has been able to clear the virus naturally. Immune cells modified in the laboratory in this way provide a test as to whether we can enhance the natural response in a useful and safe way to clear infected cells. If successful the technology could be applied to other infectious agents."
The researchers are now exploring using engineered receptors on killer T cells as a way of improving immune responses to cancer.
Yale Researchers Unravel Mystery of Brain Aneurysms
Yale researchers have taken the first critical steps in unraveling the mysteries of brain aneurysms, the often fatal rupturing of blood vessels that afflicts 500,000 people worldwide each year and nearly killed Vice President-elect Joseph Biden two decades ago.
An international team — led by Murat Gunel, professor of neurosurgery and neurobiology, and Richard Lifton, Sterling Professor and chair of genetics, and a Howard Hughes Medical Institute investigator — scanned the genomes of more than 2,000 individuals suffering from intracranial aneurysms along with 8,000 healthy subjects. They discovered three chromosome segments, or loci, where common genetic variations can create significant risk for ruptured aneurysms, which in turn cause strokes. The subjects came from hospitals in Finland, the Netherlands and Japan, and the results were similar in all groups, indicating that these variations increase risk among diverse human populations.
The findings, reported online in the journal Nature Genetics, could lead to new screening tests to identify hundreds of thousands of people at risk for strokes caused by bleeding and point to new therapies that might be able to strengthen blood vessels in the brain before they burst.
"Even though we have made significant strides in treating unruptured aneurysms, until now we have not had an effective means of identifying the majority of individuals at risk of developing this deadly problem. These genetic findings provide a starting point for changing that equation," Gunel said.
The median age when hemorrhagic stroke occurs is 50 years old, and usually there are no warning signs. In the majority of cases, the resulting strokes cause death or severe brain damage. Without an understanding of the cause of these events, physicians have been left to respond after the fact, once the damage has largely been done. Biden was one of the lucky individuals who survived a ruptured aneurysm with minimal damage - although at the time he was stricken, his condition was thought to be grave enough that a priest was summoned to confer last rites.
The Yale study showed that the risk of harboring an aneurysm increased with the number of risk variants, or alleles. Individuals with the highest number of risk alleles tripled their risk of an aneurysm, researchers found.
Based on this large collaborative study, a screening test may one day be able to identify those who are at higher risk of forming brain aneurysms or suffering a bleeding stroke as a result.
"These findings provide fundamental insights into the genetic and biochemical changes that cause this devastating brain disease, providing hope that we may also be able to provide preventive therapy before rupture occurs," Lifton said.
For instance, the new findings implicate variations in the gene SOX17, which is known to play a crucial role in the early development and repair of endothelial cells that make up the arterial walls of blood vessels. "These variations may interfere with the ability to produce cells that repair damage to the blood vessels, suggesting a path forward for developing new approaches to prevention," Gunel said.
Honeycomb to Mend a Broken Heart
A biodegradable honeycomb laced with stem cells could help broken hearts mend themselves. The polymer patch could one day lay down a pathway in areas damaged by heart disease for cells to regenerate and regrow, while the mesh itself slowly disintegrates within the body.
Such "tissue scaffolds" already exist to regenerate cartilage tissue. Heart tissue is more difficult to grow artificially, however, because the cells must be aligned in the same direction as existing fibres for the heart to beat properly. Previous attempts had left the cells growing in a more haphazard fashion.
A team from the Harvard-MIT Division of Health Sciences and Technology and the Draper Laboratory in Cambridge, Massachusetts, attempted to solve this by building a honeycomb scaffold that mimics the structural properties of heart tissue. The scaffold is made from a polymer sheet and zapped with a laser to form a honeycomb structure of individual pores, each shaped like a concertina roughly 500 micrometres long.
The team seeded the walls of the honeycomb with heart cells from 2-day-old rats and incubated the patch in an oxygen- and nutrient-rich solution for a week. Microscope images showed that the cells had begun to proliferate. "They had oriented themselves along the long axis," says Lisa Freed, who led the team.
The team think this is because the cells build up layers starting from the walls and growing towards the centre. With the honeycomb shape, this eventually led to an oval ring of cells within the pore – with the majority aligned along the long axis. A similar honeycomb, made from squares rather than tiny "concertinas", had no such preferred direction.
All together now
The cells had also formed electrical connections with one another, allowing them to contract in coordination – and when an electric field was applied along the long axis of the honeycomb, the cells indeed contracted. "You could see the cells 'beating' on the scaffold," says George Engelmayr, who also worked on the scaffolds.
When an electric current was applied along the perpendicular axis, the cells did not contract so readily. This replicates the way healthy heart tissue will contract in only one direction.
For the moment, the team believe the technology could be used to grow artificial heart tissue for screening new drugs to regulate heart activity. But in the future, the scaffold could be inserted into the body to repair damaged tissue. Since the honeycomb is flexible and stretches like heart tissue, the patch should be able to be integrated without causing additional damage.
Julia Polak from Imperial College London in the UK believes this is a big step towards creating a scaffold for damaged heart tissue. However, she points out that it could be tricky to ensure the patch exactly matches the alignment of fibres within the recipient's heart.
18:00 02 November 2008
NewScientist.com news service
David Robson
Gene Regulates Uric Acid in Humans and Bladder Stones in Dogs
A gene mutation that causes high levels of uric acid in all Dalmatian dogs and bladder stones in some Dalmatians, has been identified by a team of researchers in the School of Veterinary Medicine at the University of California, Davis. The discovery equips dog breeders with the tools to eliminate that trait from the Dalmatian breed and yields clues to the cause of similar problems in humans. The findings will be published Nov. 7 in the scientific journal Public Library of Science. "This defect, which in dogs is peculiar to the entire Dalmatian breed, has been reported for nearly a century and was probably unintentionally introduced as breeders worked to select more distinctive spotting patterns," said veterinary geneticist Danika Bannasch, lead author on the study. "It is now possible that this trait can be removed from the breed by crossing Dalmatians with the normal offspring of the original Dalmatian-pointer breeding that occurred in the early 1970s," she said. By Dec. 1, the Veterinary Genetics Laboratory in UC Davis' School of Veterinary Medicine will begin offering DNA testing for the mutation in dogs to allow breeders to eliminate the trait.
All mammals excrete waste products in their urine, but only humans, great apes and Dalmatian dogs always produce elevated levels of uric acid in their urine and blood. Other dog breeds do not usually produce uric acid. In humans, this can result in kidney stones, hypertension and gout, a painful inflammation of the joints. In Dalmatians, high uric acid levels result in the formation of bladder stones that often have to be removed surgically. Scientists have known since the early 1900s that all Dalmatians have this trait; however, the gene responsible has remained elusive.
Researchers collected DNA samples as well as urine samples from hundreds of dogs to identify the gene responsible for high levels of uric acid. Genetic analysis of dogs that are a cross between pointers and Dalmatians revealed that gene to be SLC2A9, a gene that recently has been reported to be important in regulating uric acid levels in humans. DNA analysis showed that mutations in the SLC2A9 gene were responsible for the elevated uric acid in the Dalmatians. The same mutations also were present in some bulldogs and black Russian terriers, breeds that are not known to be closely related to Dalmatians. This suggests that the gene mutation must be quite old, even predating formation of the Dalmatian breed. Alternatively, the mutation could have been introduced to those breeds by crosses between breeds, the researchers noted.
Although humans also carry the SLC2A9 gene, scientists have not yet identified the exact mechanism that causes humans and great apes to have elevated uric acid levels. The recent identification of the responsible gene mutation in dogs will help scientists better understand the related problem in humans.
Nerve Stimulation (VNS) have been shown to be effective in the management of psychiatric disorders such as depression, bipolar disorders, post-traumatic stress disorder, and drug addition, as well as for therapies of neurological diseases such as Parkinson's disease, Alzheimer's disease, Tourette Syndrome, epilepsy, dystonia, stuttering, tinnitus, recovery of cognitive and motor function following stroke, and chronic pain. Up until now, these two techniques have captured the attention of physicians and scientists; however, these therapies still pose risks to patients because they require the surgical implantation of stimulating electrodes. Thus, these types of therapies are often only available to patients presenting the worst of prognoses.
One prior stumbling block to using ultrasound noninvasively in the brain has been the skull. However, the acoustic frequencies utilized by Tyler and his colleagues to construct their pulsed ultrasound waveforms, overlap with a frequency range where optimal energy gains are achieved between transcranial transmission and brain absorption of ultrasound – which allows the ultrasound to penetrate bone and yet prevent damage to the soft tissues. Their findings are supported by other studies examining the potential of high-intensity focused ultrasound for ablating brain tissues, where it was shown that low-frequency ultrasound could be focused through human skulls.
When asked about the potential of using his groups' methods to remotely control brain activity, Tyler says: "One might be able to envision potential applications ranging from medical interventions to use in video gaming or the creation of artificial memories along the lines of Arnold Schwarzenegger's character in 'Total Recall.' Imagine taking a vacation without actually going anywhere?
"Obviously, we need to conduct further research and development, but one of the most exhilarating prospects is that low intensity, low frequency ultrasound permit deep-brain stimulation procedures without requiring exogenous proteins or surgically implanted medical devices," he adds.
Tyler and the other ASU researchers will now focus on further characterization of the influence of ultrasound on intact brain circuits and translational research, taking low intensity ultrasound from the lab into pre-clinical trials and treatment of neurological diseases.
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