Video game designers are always striving to make games more lifelike, but they'll have a hard time topping what Stanford researcher Ingmar Riedel-Kruse is up to. He's introducing life itself into games.
Riedel-Kruse and his lab group have developed the first video games in which a player's actions influence the behavior of living microorganisms in real time - while the game is being played.
These "biotic games" involve a variety of basic biological processes and some simple single-celled organisms (such as paramecia) in combination with biotechnology.
The goal is for players to have fun interacting with biological processes, without dealing with the rigor of conducting a formal experiment, said Riedel-Kruse, an assistant professor of bioengineering.
"We hope that by playing games involving biology of a scale too small to see with the naked eye, people will realize how amazing these processes are and they'll get curious and want to know more," he said.
"The applications we can envision so far are on the one hand educational, for people to learn about biology, but we are also thinking perhaps we could have people running real experiments as they play these games.
"That is something to figure out for the future, what are good research problems which a lay person could really be involved in and make substantial contributions. This approach is often referred to as crowd-sourcing."
Applying their lab equipment and knowledge to game development, Riedel-Kruse's group came up with eight games falling broadly into three classes, depending on whether players directly interact with biological processes on the scale of molecules, single cells or colonies of single cells.
The results of their design efforts are presented in a paper published in the 10th anniversary issue of Lab on a Chip (the first issue of 2011), published by the Royal Society of Chemistry. The paper is available online now.
Initially, Riedel-Kruse said, the researchers just wanted to see whether they could design such biotic games at all, so this first round of development produced fairly simple games.
"We tried to mimic some classic video games," he said. For example, one game in which players guide paramecia to "gobble up" little balls, a la PacMan, was christened PAC-mecium. Then there is Biotic Pinball, POND PONG and Ciliaball. The latter game is named for the tiny hairs, called cilia, that paramecia use in a flipper-like fashion to swim around - and in the game enables kicking a virtual soccer ball.
The basic design of the games involving paramecia - the single-celled organisms used in countless biology experiments from grade school classes to university research labs - consists of a small fluid chamber within which the paramecia can roam freely. A camera sends live images to a video screen, with the "game board" superimposed on the image of the paramecia. A microprocessor tracks the movements of the paramecia and keeps score.
The player attempts to control the paramecia using a controller that is much like a typical video game controller. In some games, such as PAC-mecium, the player controls the polarity of a mild electrical field applied across the fluid chamber, which influences the direction the paramecia move. In Biotic Pinball, the player injects occasional whiffs of a chemical into the fluid, causing the paramecia to swim one direction or another.
Riedel-Kruse emphasized that paramecia, being single-celled organisms, lack a brain and the capacity to feel pain. "We are talking about microbiology with these games, very primitive life forms. We do not use any higher-level organisms," he said. "Since multiple test players raised the question of exactly where one should draw this line, these games could be a good tool to stimulate discussions in schools on bioethical issues."
The game on the molecular level involves a common laboratory technique called polymerase chain reaction, or PCR, an automated process that lets researchers make millions of copies of an organism's DNA in as little as two hours.
In this game, called PolymerRace, the player is linked to the output of a PCR machine that is running different reactions simultaneously. While the reactions are running, the players can bet on which reactions will be run the fastest.
"The game PolymerRace is inspired by horse races, where you have different jockeys riding different horses," Riedel-Kruse said. "There is a little bit of bio-molecular logic involved and a little bit of chance."
The third game uses colonies of yeast cells that players have to distinguish based on their bread-vinegar like smell - olfactory stimuli anyone can experience just by walking into a bakery.
"The idea is that while we as humans play the game, we interact with real biological processes or material," he said. His research group thinks that aspect of the games could help motivate children and even adults to learn more about biology, which is increasingly important to society.
"We would argue that modern biotechnology will influence our life at an accelerating pace, most prominently in the personal biomedical choices that we will be faced with more and more often," Riedel-Kruse said. "Therefore everyone should have sufficient knowledge about the basics of biomedicine and biotechnology. Biotic games could promote that."
Riedel-Kruse wants to maximize the educational potential of these games to enable lay people to contribute to biomedical research. The team hopes that by publishing his group's initial efforts, other researchers in the life sciences will be prompted to explore how their own research could be adapted to "biotic" video games.
Other researchers have developed biologically relevant Internet-based video games such as Fold-It, which lets players try different approaches to folding proteins, and EteRNA, developed in a collaboration between Stanford and Carnegie Mellon University, which lets players propose new molecular structures for ribonucleic acids (RNA).
Fold-It and EteRNA were developed to address specific research questions. Fold-It was strictly a simulation; and although EteRNA will actually test some proposed structures in the laboratory, the players themselves do not have direct interaction with biological processes in real time as in Riedel-Kruse's biotic games.
Part of Riedel-Kruse's continuing work will include close collaborations with Rhiju Das, an assistant professor of biochemistry at Stanford and one of the developers of EteRNA, and Daniel Schwartz, professor in the School of Education at Stanford. The three co-founded the "Bio-X.Game Center" to develop and apply biotic games to education and research.
Source:
Louis Bergeron
Stanford University
среда, 1 июня 2011 г.
Gourds Afloat: A Dated Phylogeny Reveals An Asian Origin Of The Gourd Family (Cucurbitaceae) And Numerous Oversea Dispersal Events
Knowing the geographic origin of certain plant groups is important for genetic improvement and conservation. We address the history of the economically important gourd family, Cucurbitaceae, using a multi-gene phylogeny for 114 of the 115 genera and 25% of the 960 species.
Our results reveal an Asian origin in the Late Cretaceous, followed by the repeated spread to Africa, America, and Australia via transoceanic long distance dispersal (LDD).
North American cucurbits stem from at least seven range expansions of Central and South American lineages; Madagascar was colonized 13 times from Africa; Australia was reached twelve times from Southeast Asia.
Proceedings of the Royal Society B: Biological Sciences
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.
Proceedings of the Royal Society B: Biological Sciences
Our results reveal an Asian origin in the Late Cretaceous, followed by the repeated spread to Africa, America, and Australia via transoceanic long distance dispersal (LDD).
North American cucurbits stem from at least seven range expansions of Central and South American lineages; Madagascar was colonized 13 times from Africa; Australia was reached twelve times from Southeast Asia.
Proceedings of the Royal Society B: Biological Sciences
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.
Proceedings of the Royal Society B: Biological Sciences
Recognition Given For Ground-Breaking Advancements In Digitalizing Health Data And Information
AMIA, the association for informatics professionals, honors four leaders in biomedical and health informatics on Nov. 13, 2010, with the annual presentation of its Signature Awards. The awards are to be announced on Monday, Nov. 15 at the Opening Session of AMIA's 34th Annual Symposium on Biomedical and Health Informatics in Washington, D.C., before an audience of more than 2,000 informatics professionals attending the event. Signature awards highlight extraordinary professionals working in the health industry, whose work transforms how health information and data is gathered, applied, and disseminated, and whose efforts result in elevated standards of care in the United States and beyond.
"The Signature Award recipients have made significant contributions to informatics, and in the process, have helped streamline the way data and information can be applied to patients," said AMIA Chairwoman Nancy M. Lorenzi, PhD, Assistant Vice Chancellor for Health Affairs, Vanderbilt University Medical Center. "This group of Signature Award recipients joins an impressive cohort of pioneers in health who are leading the way to more robust biomedical research, a more responsive public health sector, advancements moving more quickly and efficiently from bench to bedside, and more incisive clinical practice - all of which are made possible through the science of informatics," she added.
The Signature Awards and recipients are:
New Investigator Award
Recognizes an individual for early informatics contributions and significant scholarly contributions of scientific merit and demonstrated research excellence.
Adam Wright, PhD, is a research scientist in the Division of General Medicine at Brigham and Women's Hospital, Boston, and an instructor at Harvard Medical School. Dr. Wright focuses on clinical decision-support systems and data mining. He develops innovative tools for automated summarization of electronic health records (EHRs), and processing tools to support physicians as they document structured information in real time. He is the principal investigator for the Making Accurate Problem Lists in the EHR (MAPLE) project, which uses structured data in medical records to predict diagnoses and advise physicians of potential gaps in documentation of care. He also conducts research on malpractice, focusing on the use of decision-support systems to mitigate malpractice risk.
Virginia K. Saba Informatics Award
Recognizes a distinguished career that has made significant impact on the care of patients and the discipline of nursing. Recipient must demonstrate: use of informatics as transformative in patient care; visionary leadership; and enduring contribution to professional practice, education, administration, research, and/or health policy.
Judy Ozbolt, , PhD, RN, is a nursing informatics pioneer, whose long career includes faculty positions at the Universities of South Carolina, Pittsburgh, Michigan, Virginia, and Maryland, and at Vanderbilt University, and service as a Scholar at the Institute of Medicine. She led Nursing Terminology Summits from 1999 to 2008, which contributed substantially to the adoption of standards for nursing data by national and international standards organizations. Most recently, she chaired a Technical Expert Panel of a project commissioned by the Office of the National Coordinator of Health Information Technology to predict and mitigate unintended consequences of EHR adoption. Dr. Ozbolt was a founding board member of AMIA, the first chair of its Nursing Informatics Working Group, and a founding member of the editorial board of JAMIA. She also is a Fellow and past president of the American College of Medical Informatics, a Fellow of the American Academy of Nursing, and a Founding Fellow of the American Institute for Medical and Biological Engineering.
Don Eugene Detmer Award for Health Policy Contributions in Informatics
Recognizes an individual who has made a significant contribution over the course of a career in health policy, conducted in accordance with the philosophy that all citizens and populations deserve a state-of-the-art health system that provides safe, effective, patient-centered, timely, efficient, and equitable health care services. The recipient exemplifies visionary leadership in the health policy realm, action-oriented advocacy work producing a regional, national or global result, advancement in thought leadership, and generating a sustainable contribution to the health system.
David Bates, MD, MSc, is chief of the Division of General Medicine at the Brigham and Women's Hospital, Boston; medical director of Clinical and Quality Analysis, IS; and a professor at both Harvard's Medical School and its School of Public Health. Dr. Bates has done extensive work evaluating the incidence and prevention of adverse drug events, and in improving efficiency and quality of diagnostic testing using information systems. He is currently evaluating the impact of guidelines on the delivery of quality of care, using electronic medical records. His work focuses on how to help clinicians make better decisions to produce more efficient, higher quality, and safer care, using information technology.
Donald A.B. Lindberg Award for Innovation in Informatics
Recognizes an individual for a specific technological, research, or educational contribution that advances biomedical informatics. The recipient's work will have been conducted in a nonprofit setting, and the adoption of the particular advance will be on a national or international level.
Carol Friedman, PhD, is a professor of Biomedical Informatics at Columbia University. Her work has demonstrated that a general natural language processing system could be used to improve clinical care and to advance understanding of medicine. Dr. Friedman developed a comprehensive natural language extraction and encoding system for the clinical domain called MedLEE, which has been in use at New York-Presbyterian Hospital, and which has been shown not only to behave similarly to medical experts but also to improve actual patient care. In collaboration, she adapted MedLEE into a natural language processing system called GENIES, which extracts biomolecular relations from journal articles to obtain data on molecular pathways. From there, she went on to co-develop the BioMedLEE system, another adaptation of MedLEE, which extracts a broad range of genotypic-phenotypic relations from the literature, and maps the extracted information to an ontology appropriate for biology. Dr. Friedman is currently working on research in the area of patient safety, using data from clinical narrative notes to detect novel adverse drug events.
Source:
Nancy Light
American Medical Informatics Association
"The Signature Award recipients have made significant contributions to informatics, and in the process, have helped streamline the way data and information can be applied to patients," said AMIA Chairwoman Nancy M. Lorenzi, PhD, Assistant Vice Chancellor for Health Affairs, Vanderbilt University Medical Center. "This group of Signature Award recipients joins an impressive cohort of pioneers in health who are leading the way to more robust biomedical research, a more responsive public health sector, advancements moving more quickly and efficiently from bench to bedside, and more incisive clinical practice - all of which are made possible through the science of informatics," she added.
The Signature Awards and recipients are:
New Investigator Award
Recognizes an individual for early informatics contributions and significant scholarly contributions of scientific merit and demonstrated research excellence.
Adam Wright, PhD, is a research scientist in the Division of General Medicine at Brigham and Women's Hospital, Boston, and an instructor at Harvard Medical School. Dr. Wright focuses on clinical decision-support systems and data mining. He develops innovative tools for automated summarization of electronic health records (EHRs), and processing tools to support physicians as they document structured information in real time. He is the principal investigator for the Making Accurate Problem Lists in the EHR (MAPLE) project, which uses structured data in medical records to predict diagnoses and advise physicians of potential gaps in documentation of care. He also conducts research on malpractice, focusing on the use of decision-support systems to mitigate malpractice risk.
Virginia K. Saba Informatics Award
Recognizes a distinguished career that has made significant impact on the care of patients and the discipline of nursing. Recipient must demonstrate: use of informatics as transformative in patient care; visionary leadership; and enduring contribution to professional practice, education, administration, research, and/or health policy.
Judy Ozbolt, , PhD, RN, is a nursing informatics pioneer, whose long career includes faculty positions at the Universities of South Carolina, Pittsburgh, Michigan, Virginia, and Maryland, and at Vanderbilt University, and service as a Scholar at the Institute of Medicine. She led Nursing Terminology Summits from 1999 to 2008, which contributed substantially to the adoption of standards for nursing data by national and international standards organizations. Most recently, she chaired a Technical Expert Panel of a project commissioned by the Office of the National Coordinator of Health Information Technology to predict and mitigate unintended consequences of EHR adoption. Dr. Ozbolt was a founding board member of AMIA, the first chair of its Nursing Informatics Working Group, and a founding member of the editorial board of JAMIA. She also is a Fellow and past president of the American College of Medical Informatics, a Fellow of the American Academy of Nursing, and a Founding Fellow of the American Institute for Medical and Biological Engineering.
Don Eugene Detmer Award for Health Policy Contributions in Informatics
Recognizes an individual who has made a significant contribution over the course of a career in health policy, conducted in accordance with the philosophy that all citizens and populations deserve a state-of-the-art health system that provides safe, effective, patient-centered, timely, efficient, and equitable health care services. The recipient exemplifies visionary leadership in the health policy realm, action-oriented advocacy work producing a regional, national or global result, advancement in thought leadership, and generating a sustainable contribution to the health system.
David Bates, MD, MSc, is chief of the Division of General Medicine at the Brigham and Women's Hospital, Boston; medical director of Clinical and Quality Analysis, IS; and a professor at both Harvard's Medical School and its School of Public Health. Dr. Bates has done extensive work evaluating the incidence and prevention of adverse drug events, and in improving efficiency and quality of diagnostic testing using information systems. He is currently evaluating the impact of guidelines on the delivery of quality of care, using electronic medical records. His work focuses on how to help clinicians make better decisions to produce more efficient, higher quality, and safer care, using information technology.
Donald A.B. Lindberg Award for Innovation in Informatics
Recognizes an individual for a specific technological, research, or educational contribution that advances biomedical informatics. The recipient's work will have been conducted in a nonprofit setting, and the adoption of the particular advance will be on a national or international level.
Carol Friedman, PhD, is a professor of Biomedical Informatics at Columbia University. Her work has demonstrated that a general natural language processing system could be used to improve clinical care and to advance understanding of medicine. Dr. Friedman developed a comprehensive natural language extraction and encoding system for the clinical domain called MedLEE, which has been in use at New York-Presbyterian Hospital, and which has been shown not only to behave similarly to medical experts but also to improve actual patient care. In collaboration, she adapted MedLEE into a natural language processing system called GENIES, which extracts biomolecular relations from journal articles to obtain data on molecular pathways. From there, she went on to co-develop the BioMedLEE system, another adaptation of MedLEE, which extracts a broad range of genotypic-phenotypic relations from the literature, and maps the extracted information to an ontology appropriate for biology. Dr. Friedman is currently working on research in the area of patient safety, using data from clinical narrative notes to detect novel adverse drug events.
Source:
Nancy Light
American Medical Informatics Association
Cell 'Anchors' Required To Prevent Muscular Dystrophy
A protein that was first identified for playing a key role in regulating normal heart rhythms also appears to be significant in helping muscle cells survive the forces of muscle contraction. The clue was a laboratory mouse that seemed to have a form of muscular dystrophy.
A group of proteins called ankyrins, or anchor proteins, were first discovered in human red blood cells by Vann Bennett, M.D. a Howard Hughes Medical Institute investigator and James B. Duke Professor of Cell Biology, Biochemistry, and Neurobiology. Ankyrins are a family of proteins that assist in attaching other proteins to the fragile cell membrane, and in the case of red blood cells, this helps cells resist shearing forces when blood is pumped vigorously throughout the body.
Bennett's team was exploring the function of anchor protein ankyrin-B (ankB) by knocking out gene expression of the gene that makes the protein. They found newborn mice missing ankB had splayed shoulder bones, which stuck out of the animals' backs like wings, rather than lying flat, a symptom of a muscular problem.
"I went back to my pediatric textbook and saw images of people with a form of muscular dystrophy who had splayed shoulder bones," said Bennett, "This opened our eyes to the possibility that, in addition to defects in controlling heart rhythm that we have studied before, the mice might also suffer from muscular dystrophy."
The team turned its attention to ankB with regard to muscle cell organization. They knew that people with Duchenne muscular dystrophy were missing the protein dystrophin, and that dystrophin is needed for a protein complex to form and protect the cells' thin plasma-membrane layer from forces exerted by muscle cells contracting.
"Without dystrophin, you lose the entire protective complex, but nobody knew why," Bennett said. "We have found the outlines of a pathway through which dystrophin assembled this complex. The missing piece of the puzzle was the ankyrin proteins." The work appears in Cell journal.
The protective layer is located at a very particular place on the muscle cell membrane, where costameres, riblike structures, hold the bundled muscle cells together. This is similar to a steel cables attaching to a specific point along a suspension bridge to distribute the forces and keep the flexible bridge intact, Bennett said.
When the protective protein layer isn't present, muscle contraction forces may break the cell membrane, toxins pour in and vital enzymes stream out. The muscle cells die.
The first experiment for the new study asked if the protein dystrophin was found on the cell plasma membrane in the study animals which lacked ankB. It was not.
Beta-dystroglycan, the core component of the dystrophin-glycoprotein complex that is responsible for attaching dystrophin to the muscle membrane, also was missing, which suggested that a loss of ankyrin-B is linked to a loss of at least two key proteins in the cell membrane, Bennett said.
The researchers needed to continue their studies in adult mice with fully formed muscle cells to observe them in action, because muscle cells in culture don't have properly functioning costameres. They knew, however, that knocking out ankyrin-B causes the mice to die soon after birth.
Fortunately, Gai Ayalon, Ph.D., a postdoctoral fellow in the Bennett laboratory, devised a method that let researchers manipulate gene expression in a specific section of adult muscle, rather than in the whole animal. "This development let us look right away at what happened in adult mice when we produced ankyrin loss only in leg muscle," Ayalon said.
Next, they studied what happened when they turned off ankyrin-G (ankG), a different anchor protein, in muscle cells. They found that the cells needed ankG to help dystrophin and beta-dystroglycan stay in place at the costameres.
Ayalon exercised the mice to learn how the muscle cells fared without ankG. The cells tore apart.
The researchers also discovered that ankB stabilized a set of structures found in all cells, called microtubules. These structures are like tracks for the molecular motors that carry the dystrophin molecules from the site where they are made to their specific destination. Ankyrin B helps microtubules align so dystrophin molecules can travel to the membrane and then ankyrin G holds them in place, Bennett explained.
"I'm excited because ankyrin-B's ability to anchor microtubules could have broad implications in many cell types," Bennett said.
Funding sources included the Muscular Dystrophy Association and the Howard Hughes Medical Institute. Other authors included Jonathan Q. Davis and Paula B. Scotland of the Howard Hughes Medical Institute and Dr. Bennett's laboratory at Duke in Cell Biology, Biochemistry and Neurobiology.
Source: Mary Jane Gore
Duke University Medical Center
A group of proteins called ankyrins, or anchor proteins, were first discovered in human red blood cells by Vann Bennett, M.D. a Howard Hughes Medical Institute investigator and James B. Duke Professor of Cell Biology, Biochemistry, and Neurobiology. Ankyrins are a family of proteins that assist in attaching other proteins to the fragile cell membrane, and in the case of red blood cells, this helps cells resist shearing forces when blood is pumped vigorously throughout the body.
Bennett's team was exploring the function of anchor protein ankyrin-B (ankB) by knocking out gene expression of the gene that makes the protein. They found newborn mice missing ankB had splayed shoulder bones, which stuck out of the animals' backs like wings, rather than lying flat, a symptom of a muscular problem.
"I went back to my pediatric textbook and saw images of people with a form of muscular dystrophy who had splayed shoulder bones," said Bennett, "This opened our eyes to the possibility that, in addition to defects in controlling heart rhythm that we have studied before, the mice might also suffer from muscular dystrophy."
The team turned its attention to ankB with regard to muscle cell organization. They knew that people with Duchenne muscular dystrophy were missing the protein dystrophin, and that dystrophin is needed for a protein complex to form and protect the cells' thin plasma-membrane layer from forces exerted by muscle cells contracting.
"Without dystrophin, you lose the entire protective complex, but nobody knew why," Bennett said. "We have found the outlines of a pathway through which dystrophin assembled this complex. The missing piece of the puzzle was the ankyrin proteins." The work appears in Cell journal.
The protective layer is located at a very particular place on the muscle cell membrane, where costameres, riblike structures, hold the bundled muscle cells together. This is similar to a steel cables attaching to a specific point along a suspension bridge to distribute the forces and keep the flexible bridge intact, Bennett said.
When the protective protein layer isn't present, muscle contraction forces may break the cell membrane, toxins pour in and vital enzymes stream out. The muscle cells die.
The first experiment for the new study asked if the protein dystrophin was found on the cell plasma membrane in the study animals which lacked ankB. It was not.
Beta-dystroglycan, the core component of the dystrophin-glycoprotein complex that is responsible for attaching dystrophin to the muscle membrane, also was missing, which suggested that a loss of ankyrin-B is linked to a loss of at least two key proteins in the cell membrane, Bennett said.
The researchers needed to continue their studies in adult mice with fully formed muscle cells to observe them in action, because muscle cells in culture don't have properly functioning costameres. They knew, however, that knocking out ankyrin-B causes the mice to die soon after birth.
Fortunately, Gai Ayalon, Ph.D., a postdoctoral fellow in the Bennett laboratory, devised a method that let researchers manipulate gene expression in a specific section of adult muscle, rather than in the whole animal. "This development let us look right away at what happened in adult mice when we produced ankyrin loss only in leg muscle," Ayalon said.
Next, they studied what happened when they turned off ankyrin-G (ankG), a different anchor protein, in muscle cells. They found that the cells needed ankG to help dystrophin and beta-dystroglycan stay in place at the costameres.
Ayalon exercised the mice to learn how the muscle cells fared without ankG. The cells tore apart.
The researchers also discovered that ankB stabilized a set of structures found in all cells, called microtubules. These structures are like tracks for the molecular motors that carry the dystrophin molecules from the site where they are made to their specific destination. Ankyrin B helps microtubules align so dystrophin molecules can travel to the membrane and then ankyrin G holds them in place, Bennett explained.
"I'm excited because ankyrin-B's ability to anchor microtubules could have broad implications in many cell types," Bennett said.
Funding sources included the Muscular Dystrophy Association and the Howard Hughes Medical Institute. Other authors included Jonathan Q. Davis and Paula B. Scotland of the Howard Hughes Medical Institute and Dr. Bennett's laboratory at Duke in Cell Biology, Biochemistry and Neurobiology.
Source: Mary Jane Gore
Duke University Medical Center
New Discovery May Aid In Creation Of Therapies For Visual, Hearing Problems
It's safe to say that cilia, the hairlike appendages jutting out from the smooth surfaces of most mammalian cells, have long been misunderstood - underestimated, even.
Not to be confused with their whiplike cousins flagella, which propel sperm, one type of cilia has been known to serve as microscopic conveyor belts. (Picture cilia reaching up like concertgoers supporting a crowd-surfer.) But for decades another type of cilia, known as "primary" cilia, was believed to serve little to no purpose. Despite the fact that almost every cell found in vertebrates has at least one primary cilium, the organ was regarded as merely an evolutionary relic - the cellular equivalent to the human appendix.
Of late, however, it has become increasingly clear that primary cilia serve as powerful communication hubs. (After all, they do sort of look like antennae.) Disruptions in the activity of cilia are now understood to lead to a whole class of diseases dubbed ciliopathies, and researchers are hustling to figure out what makes them tick.
One group of scientists in Japan last month marked a milestone in the pursuit to reveal cilia's secrets. In study results that were fast-tracked for publication and deemed a "Paper of the Week" by the Journal of Biological Chemistry, they report that they have identified a long-elusive enzyme necessary for the proper regulation of cilia.
The Hamamatsu University School of Medicine team is optimistic that the discovery may aid in the development of therapies for those with visual and hearing maladies caused by cilia dysfunction.
"Our finding might give insights into the sensory defects associated with problems in cilia function. For example, patients with some syndromes have genetic defects in cilia functions that result in retinal degeneration," explains Mitsutoshi Setou, who oversaw the team's work. "Also, age-dependent visual loss or hearing loss is known to be related to damage of the eye or ear sensory cilia. To enhance or suppress the activity of the newly found enzyme might alleviate the symptoms through the proper regulation of cilia."
With the hopes of one day manipulating cilia's activities on the perimeter of cells and, thus, how those activities affect human health, the team traced cilia's molecular roots into the depths of cells themselves.
If a cilium had a life story, it would begin with a gene. That gene encodes information during a cell's production of tubulin proteins so that they will link up into microtubules, or tiny tubes, and form the interior apparatus of a protruding cilium.
Scientists have known for some time that a group of enzymes can indirectly affect what goes on inside cilia by adding unusually branched chains of amino acids, known as glutamates, onto certain spots of the tubulin proteins that make up the microtubules. Suspecting that the addition of the amino acid chains on the tubulin building blocks might influence how material is transported within cilia, Setou's team took a closer look at how and where the chains of amino acids are added to tubulin proteins and set out to figure out what, ultimately, removed those same chains.
To do so, they analyzed cilia on cells of sensory neurons in a living model organism, the roundworm, and studied purified protein from cultured mouse cells. Ultimately, the enzyme that strips the amino acid chains was elusive no more.
"We found out which enzyme removes part of the glutamate chain, and we now have a better understanding of that lengthening and shortening of amino acids on tubulin that regulates the function of cilia in sensory nerves," he said.
Setou is hopeful the finding will help develop therapies for a group of genetic diseases known as retinitis pigmentosa, which causes degeneration of the eye's retina and, thus, progressive loss of sight.
The human photoreceptor is a sensory neuron composed of two segments that are connected by a cilium responsible for transporting proteins from one end to the other. If that protein movement slows down or stops due to cilium malfunction, the protein accumulates abnormally and induces retinal cell death.
"Retinitis pigmentosa is one of the leading causes of adult vision loss, and yet there is no cure for it," he said. "Recent studies have shown that at least 35 genes are involved. Importantly, some of them are related to cilia formation and maintenance. This important function of cilia could be regulated by the level of polyglutamylation, which is controlled by the level of newly found enzyme."
While Setou's team focused exclusively on cilia found in sensory neurons for their experiments, the findings may prove useful in other types of cilia as well. Defective cilia lining the kidney, for example, can lead to polycystic kidney disease. Mammals rely on cilia lining reproductive organs: If there are too few functional cilia in the Fallopian tubes, which are tasked with moving a fertilized egg into proper position for growth, the ovum may hunker down too soon, causing a tubal pregnancy. Meanwhile, what are known as chemoreceptor cilia, found on olfactory neurons, detect odor.
The team's research was funded by the Japan Science and Technology Agency and the Japan Society for the Promotion of Science. The resulting "Paper of the Week" was published on the Journal of Biological Chemistry's website June 2 will appear in the July 23 issue.
The project participants included Yoshishige Kimura, Nobuya Kurabe, Koji Ikegami, Koji Tsutsumi, Yoshiyuki Konishi, Oktay Ismail Kaplan, Oliver E. Blacque, Hirofumi Kunitomo and Yuichi Iino.
Source:
Angela Hopp
American Society for Biochemistry and Molecular Biology
Not to be confused with their whiplike cousins flagella, which propel sperm, one type of cilia has been known to serve as microscopic conveyor belts. (Picture cilia reaching up like concertgoers supporting a crowd-surfer.) But for decades another type of cilia, known as "primary" cilia, was believed to serve little to no purpose. Despite the fact that almost every cell found in vertebrates has at least one primary cilium, the organ was regarded as merely an evolutionary relic - the cellular equivalent to the human appendix.
Of late, however, it has become increasingly clear that primary cilia serve as powerful communication hubs. (After all, they do sort of look like antennae.) Disruptions in the activity of cilia are now understood to lead to a whole class of diseases dubbed ciliopathies, and researchers are hustling to figure out what makes them tick.
One group of scientists in Japan last month marked a milestone in the pursuit to reveal cilia's secrets. In study results that were fast-tracked for publication and deemed a "Paper of the Week" by the Journal of Biological Chemistry, they report that they have identified a long-elusive enzyme necessary for the proper regulation of cilia.
The Hamamatsu University School of Medicine team is optimistic that the discovery may aid in the development of therapies for those with visual and hearing maladies caused by cilia dysfunction.
"Our finding might give insights into the sensory defects associated with problems in cilia function. For example, patients with some syndromes have genetic defects in cilia functions that result in retinal degeneration," explains Mitsutoshi Setou, who oversaw the team's work. "Also, age-dependent visual loss or hearing loss is known to be related to damage of the eye or ear sensory cilia. To enhance or suppress the activity of the newly found enzyme might alleviate the symptoms through the proper regulation of cilia."
With the hopes of one day manipulating cilia's activities on the perimeter of cells and, thus, how those activities affect human health, the team traced cilia's molecular roots into the depths of cells themselves.
If a cilium had a life story, it would begin with a gene. That gene encodes information during a cell's production of tubulin proteins so that they will link up into microtubules, or tiny tubes, and form the interior apparatus of a protruding cilium.
Scientists have known for some time that a group of enzymes can indirectly affect what goes on inside cilia by adding unusually branched chains of amino acids, known as glutamates, onto certain spots of the tubulin proteins that make up the microtubules. Suspecting that the addition of the amino acid chains on the tubulin building blocks might influence how material is transported within cilia, Setou's team took a closer look at how and where the chains of amino acids are added to tubulin proteins and set out to figure out what, ultimately, removed those same chains.
To do so, they analyzed cilia on cells of sensory neurons in a living model organism, the roundworm, and studied purified protein from cultured mouse cells. Ultimately, the enzyme that strips the amino acid chains was elusive no more.
"We found out which enzyme removes part of the glutamate chain, and we now have a better understanding of that lengthening and shortening of amino acids on tubulin that regulates the function of cilia in sensory nerves," he said.
Setou is hopeful the finding will help develop therapies for a group of genetic diseases known as retinitis pigmentosa, which causes degeneration of the eye's retina and, thus, progressive loss of sight.
The human photoreceptor is a sensory neuron composed of two segments that are connected by a cilium responsible for transporting proteins from one end to the other. If that protein movement slows down or stops due to cilium malfunction, the protein accumulates abnormally and induces retinal cell death.
"Retinitis pigmentosa is one of the leading causes of adult vision loss, and yet there is no cure for it," he said. "Recent studies have shown that at least 35 genes are involved. Importantly, some of them are related to cilia formation and maintenance. This important function of cilia could be regulated by the level of polyglutamylation, which is controlled by the level of newly found enzyme."
While Setou's team focused exclusively on cilia found in sensory neurons for their experiments, the findings may prove useful in other types of cilia as well. Defective cilia lining the kidney, for example, can lead to polycystic kidney disease. Mammals rely on cilia lining reproductive organs: If there are too few functional cilia in the Fallopian tubes, which are tasked with moving a fertilized egg into proper position for growth, the ovum may hunker down too soon, causing a tubal pregnancy. Meanwhile, what are known as chemoreceptor cilia, found on olfactory neurons, detect odor.
The team's research was funded by the Japan Science and Technology Agency and the Japan Society for the Promotion of Science. The resulting "Paper of the Week" was published on the Journal of Biological Chemistry's website June 2 will appear in the July 23 issue.
The project participants included Yoshishige Kimura, Nobuya Kurabe, Koji Ikegami, Koji Tsutsumi, Yoshiyuki Konishi, Oktay Ismail Kaplan, Oliver E. Blacque, Hirofumi Kunitomo and Yuichi Iino.
Source:
Angela Hopp
American Society for Biochemistry and Molecular Biology
Rare 'Gene-For-Gene' Interaction That Helps Bacteria Kill Their Host, Discovered By Scientists
Scientists have discovered that a cousin of the plague bacterium uses a single gene to out-fox insect immune defences and kill its host.
In research published in the journal Proceedings of the National Academy of Science, scientists have found that Photorhabdus bacteria produce an antibiotic which inhibits the work of an enzyme that insects' immune systems use to defend themselves from attack.
Although such so-called gene-for-gene interactions are thought to be common in diseases, very few examples of a single gene in a pathogen targeting a single gene in an animal or human host have been identified so far.
Photorhabdus is a family of bacteria that in relatively small concentrations can kill insects - between 10-100 cells of it are typically enough - but most are harmless to humans and can be used as a biological control mechanism to replace pesticide use.
The researchers, from the universities of Bath, Bristol and Exeter, all in the UK, used the large caterpillar Manduca sexta (tobacco hornworm) to study the bacteria's so-called virulence genes.
"The beauty of this research is that we have been able to study the whole genome of the bacteria to work out how it kills its host," said Professor Stuart Reynolds from the University of Bath.
"People studying diseases think that the kind of gene-for-gene interaction between pathogen and host that we have found is quite common, but actually rather few are known, which is why this research is so interesting.
"The immune systems of all animals, even relatively simple ones like insects, are all very similar.
"This is particularly true of the innate immune system, which is the fast-acting battery of defences that recognise and kill microbes to prevent infections from occurring.
"Some remarkable discoveries have been made using insects that have subsequently allowed important advances in understanding how the human immune system works."
As part of their innate immune system, insects use an enzyme called phenoloxidase to produce reactive molecules that kill bacteria and then encapsulate them in a dense coat of black pigment called melanin.
The researchers found that Photorhabdus produces a special phenoloxidase inhibitor to protect itself against this particular defence.
They identified the inhibitor as a small molecule called 1,3-dihydroxy-2-(isopropyl)-5-(2-phenylethenyl)benzene, known as ST for short.
This molecule is also an antibiotic and Photorhabdus produces it to kill off other microbes that might grow in the corpse of the dead insect.
To test their findings, the researchers produced a mutant Photorhabdus that is unable to make ST. Without ST, the bacteria were less virulent. The researchers then used a technique known RNA interference to prevent the insects from producing the phenoloxidase enzyme. These insects were more susceptible to regular Photorhabdus bacteria.
But when the two were combined, it was found that not being able to produce ST made no difference to Photorhabdus when colonising insects unable to produce phenoloxidase.
"This is conclusive evidence for a gene-for-gene interaction between the bacterium and the insect," said Richard ffrench-Constant (correct) of Exeter University.
"Photorhabdus is an important biocontrol organism that is used to control insect pests and reduces pesticide use, so the more we know about it, the more useful it can be.
"Insects are the major players in almost every ecosystem on the planet, so we need to know as much as we can about them."
The research was supported through the Exploiting Genomics initiative funded by the Biotechnology & Biological Sciences Research Council (UK).
Source: 'An antibiotic produced by an insect-pathogenic bacterium suppresses host defenses through phenoloxidase inhibition,' Ioannis Eleftherianos, Sam Boundy, Susan A. Joyce, Shazia Aslam, James W. Marshall, Russell J. Cox, Thomas J. Simpson, David J. Clarke, Richard H. ffrench-Constant, and Stuart E. Reynolds, PNAS 2007 104: 2419-2424
Notes
The University of Bath is one of the UK's leading universities, with an international reputation for quality research and teaching. In 20 subject areas the University of Bath is rated in the top ten in the country. View a full list of the University's press releases: bath.ac.uk/pr/releases
Contact: Andrew McLaughlin
University of Bath
In research published in the journal Proceedings of the National Academy of Science, scientists have found that Photorhabdus bacteria produce an antibiotic which inhibits the work of an enzyme that insects' immune systems use to defend themselves from attack.
Although such so-called gene-for-gene interactions are thought to be common in diseases, very few examples of a single gene in a pathogen targeting a single gene in an animal or human host have been identified so far.
Photorhabdus is a family of bacteria that in relatively small concentrations can kill insects - between 10-100 cells of it are typically enough - but most are harmless to humans and can be used as a biological control mechanism to replace pesticide use.
The researchers, from the universities of Bath, Bristol and Exeter, all in the UK, used the large caterpillar Manduca sexta (tobacco hornworm) to study the bacteria's so-called virulence genes.
"The beauty of this research is that we have been able to study the whole genome of the bacteria to work out how it kills its host," said Professor Stuart Reynolds from the University of Bath.
"People studying diseases think that the kind of gene-for-gene interaction between pathogen and host that we have found is quite common, but actually rather few are known, which is why this research is so interesting.
"The immune systems of all animals, even relatively simple ones like insects, are all very similar.
"This is particularly true of the innate immune system, which is the fast-acting battery of defences that recognise and kill microbes to prevent infections from occurring.
"Some remarkable discoveries have been made using insects that have subsequently allowed important advances in understanding how the human immune system works."
As part of their innate immune system, insects use an enzyme called phenoloxidase to produce reactive molecules that kill bacteria and then encapsulate them in a dense coat of black pigment called melanin.
The researchers found that Photorhabdus produces a special phenoloxidase inhibitor to protect itself against this particular defence.
They identified the inhibitor as a small molecule called 1,3-dihydroxy-2-(isopropyl)-5-(2-phenylethenyl)benzene, known as ST for short.
This molecule is also an antibiotic and Photorhabdus produces it to kill off other microbes that might grow in the corpse of the dead insect.
To test their findings, the researchers produced a mutant Photorhabdus that is unable to make ST. Without ST, the bacteria were less virulent. The researchers then used a technique known RNA interference to prevent the insects from producing the phenoloxidase enzyme. These insects were more susceptible to regular Photorhabdus bacteria.
But when the two were combined, it was found that not being able to produce ST made no difference to Photorhabdus when colonising insects unable to produce phenoloxidase.
"This is conclusive evidence for a gene-for-gene interaction between the bacterium and the insect," said Richard ffrench-Constant (correct) of Exeter University.
"Photorhabdus is an important biocontrol organism that is used to control insect pests and reduces pesticide use, so the more we know about it, the more useful it can be.
"Insects are the major players in almost every ecosystem on the planet, so we need to know as much as we can about them."
The research was supported through the Exploiting Genomics initiative funded by the Biotechnology & Biological Sciences Research Council (UK).
Source: 'An antibiotic produced by an insect-pathogenic bacterium suppresses host defenses through phenoloxidase inhibition,' Ioannis Eleftherianos, Sam Boundy, Susan A. Joyce, Shazia Aslam, James W. Marshall, Russell J. Cox, Thomas J. Simpson, David J. Clarke, Richard H. ffrench-Constant, and Stuart E. Reynolds, PNAS 2007 104: 2419-2424
Notes
The University of Bath is one of the UK's leading universities, with an international reputation for quality research and teaching. In 20 subject areas the University of Bath is rated in the top ten in the country. View a full list of the University's press releases: bath.ac.uk/pr/releases
Contact: Andrew McLaughlin
University of Bath
Nerve Structures, Or Constructs, Created In Culture: Implications For Repairing Spinal Cord Injury
Researchers at the University of Pennsylvania School of Medicine have created - in a rodent model - a completely new way to engineer nerve structures, or constructs, in culture. This proof-of-principle research has implications for eventually becoming a new method to repair spinal cord injury in humans. The work appears in the latest issue of Tissue Engineering.
"We have created a three-dimensional neural network, a mini nervous system in culture, which can be transplanted en masse," explains senior author Douglas H. Smith, MD, Professor, Department of Neurosurgery and Director of the Center for Brain Injury and Repair at Penn. Previously, Smith's group showed that they could grow axons by placing neurons from rat dorsal root ganglia (clusters of nerves just outside the spinal cord) on nutrient-filled plastic plates. Axons sprouted from the neurons on each plate and connected with neurons on the other plate. The plates were then slowly pulled apart over a series of days, aided by a precise computer-controlled motor system.
In this study, the neurons were elongated to 10mm over seven days - after which they were embedded in a collagen matrix (with growth factors), rolled into a form resembling a jelly roll, and then implanted into a rat model of spinal cord injury.
"That creates what we call a nervous-tissue construct," says Smith. "We have designed a geometrical arrangement that looks similar to the longitudinal arrangement that the spinal cord had before it was damaged. The long bundles of axons span two populations of neurons, and these neuron constructs can grow axons in two directions - toward each other and into the host spinal cord at each side. That way they can integrate and connect the 'cables' to the host tissue in order to bridge a spinal cord lesion."
After the four-week study period, the researchers found that the geometry of the construct was maintained and that the neurons at both ends and all the axons spanning these neurons survived transplantation. More importantly, the axons at the ends of the construct adjacent to the host tissue did extend through the collagen barrier, penetrating into the host tissue. Future studies will measure neuronal electrical conductivity across the newly engineered bridge and restoration of motor activity.
"The really great news - and there's still much work to be done - is that the construct survives and also integrates with host tissue," says Smith. "We find this very promising. In particular, this new technique provides a means to bridge even very long spinal lesions that are common in humans with spinal cord injury. Now we have to test whether the transplanted constructs convey a signal all the way through, and we're developing and testing a new animal model to allow us to test whether this new technique improves function."
Study co-authors are Akira Iwata, Kevin D. Browne, Bryan J. Pfister, all from Penn; and John A. Gruner, from Cephalon Inc., West Chester, PA. The research was funded by the National Institutes of Health and the Sharpe Trust.
This release and related images can be found at uphs.upenn/news/
PENN Medicine is a $2.7 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System comprises: its flagship hospital, the Hospital of the University of Pennsylvania, consistently rated one of the nation's "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; Penn Presbyterian Medical Center; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home health care and hospice.
Contact: Karen Kreeger
karen.kreegeruphs.upenn
University of Pennsylvania School of Medicine
"We have created a three-dimensional neural network, a mini nervous system in culture, which can be transplanted en masse," explains senior author Douglas H. Smith, MD, Professor, Department of Neurosurgery and Director of the Center for Brain Injury and Repair at Penn. Previously, Smith's group showed that they could grow axons by placing neurons from rat dorsal root ganglia (clusters of nerves just outside the spinal cord) on nutrient-filled plastic plates. Axons sprouted from the neurons on each plate and connected with neurons on the other plate. The plates were then slowly pulled apart over a series of days, aided by a precise computer-controlled motor system.
In this study, the neurons were elongated to 10mm over seven days - after which they were embedded in a collagen matrix (with growth factors), rolled into a form resembling a jelly roll, and then implanted into a rat model of spinal cord injury.
"That creates what we call a nervous-tissue construct," says Smith. "We have designed a geometrical arrangement that looks similar to the longitudinal arrangement that the spinal cord had before it was damaged. The long bundles of axons span two populations of neurons, and these neuron constructs can grow axons in two directions - toward each other and into the host spinal cord at each side. That way they can integrate and connect the 'cables' to the host tissue in order to bridge a spinal cord lesion."
After the four-week study period, the researchers found that the geometry of the construct was maintained and that the neurons at both ends and all the axons spanning these neurons survived transplantation. More importantly, the axons at the ends of the construct adjacent to the host tissue did extend through the collagen barrier, penetrating into the host tissue. Future studies will measure neuronal electrical conductivity across the newly engineered bridge and restoration of motor activity.
"The really great news - and there's still much work to be done - is that the construct survives and also integrates with host tissue," says Smith. "We find this very promising. In particular, this new technique provides a means to bridge even very long spinal lesions that are common in humans with spinal cord injury. Now we have to test whether the transplanted constructs convey a signal all the way through, and we're developing and testing a new animal model to allow us to test whether this new technique improves function."
Study co-authors are Akira Iwata, Kevin D. Browne, Bryan J. Pfister, all from Penn; and John A. Gruner, from Cephalon Inc., West Chester, PA. The research was funded by the National Institutes of Health and the Sharpe Trust.
This release and related images can be found at uphs.upenn/news/
PENN Medicine is a $2.7 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System comprises: its flagship hospital, the Hospital of the University of Pennsylvania, consistently rated one of the nation's "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; Penn Presbyterian Medical Center; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home health care and hospice.
Contact: Karen Kreeger
karen.kreegeruphs.upenn
University of Pennsylvania School of Medicine
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