New research reveals that when cells move about in the body, they follow a complex pattern similar to that which amoebae and bacteria use when searching for food
ScienceDaily.com, March 22, 2010 — When cells move about in the body, they follow a complex pattern similar to that which amoebae and bacteria use when searching for food, a team of Vanderbilt researchers has found.
The discovery has a practical value for drug development: Incorporating this basic behavior into computer simulations of biological processes that involve cell migration, such as embryo development, bone remodeling, wound healing, infection and tumor growth, should improve the accuracy with which these models can predict the effectiveness of untested therapies for related disorders, the researchers say.
“As far as we can tell, this is the first time this type of behavior has been reported in cells that are part of a larger organism,” says Peter T. Cummings, John R. Hall Professor of Chemical Engineering, who directed the study that is described in the March 10 issue of the Public Library of Science journal PLoS ONE.
The discovery was the unanticipated result of a study the Cummings group conducted to test the hypothesis that the freedom with which different cancer cells move — a concept called motility — could be correlated with their aggressiveness: That is, the faster a given type of cancer cell can move through the body the more aggressive it is.
“Our results refute that hypothesis — the correlation between motility and aggressiveness that we found among three different types of cancer cells was very weak,” Cummings says. “In the process, however, we began noticing that the cell movements were unexpectedly complicated.”
Then the researchers’ interest was piqued by a paper that appeared in the February 2008 issue of the journal Nature titled, “Scaling laws of marine predator search behaviour.” The paper contained an analysis of the movements of a variety of radio-tagged marine predators, including sharks, sea turtles and penguins. The authors found that the predators used a foraging strategy very close to a specialized random walk pattern, called a Lévy walk, an optimal method for searching complex landscapes. At the end of the paper’s abstract they wrote, “…Lévy-like behaviour seems to be widespread among diverse organisms, from microbes to humans, as a ‘rule’ that evolved in response to patchy resource distributions.”
This gave Cummings and his colleagues a new perspective on the cell movements that they were observing in the microscope. They adopted the basic assumption that when mammalian cells migrate they face problems, such as efficiently finding randomly distributed targets like nutrients and growth factors, that are analogous to those faced by single-celled organisms foraging for food.
With this perspective in mind, Alka Potdar, now a post-doctoral fellow at Case Western Reserve University and the Cleveland Clinic, cultured cells from three human mammary epithelial cell lines on two-dimensional plastic plates and tracked the cell motions for two-hour periods in a “random migration” environment free of any directional chemical signals. Epithelial cells are found throughout the body lining organs and covering external surfaces. They move relatively slowly, at about a micron per minute which corresponds to two thousandths of an inch per hour.
When Potdar carefully analyzed these cell movements, she found that they all followed the same pattern. However, it was not the Lévy walk that they expected, but a closely related search pattern called a bimodal correlated random walk (BCRW). This is a two-phase movement: a run phase in which the cell travels primarily in one direction and a re-orientation phase in which it stays in place and reorganizes itself internally to move in a new direction.
In subsequent studies, currently in press, the researchers have found that several other cell types (social amoeba, neutrophils, fibrosarcoma) also follow the same pattern in random migration conditions. They have also found that the cells continue to follow this same basic pattern when a directional chemical signal is added, but the length of their runs are varied and the range of directions they follow are narrowed giving them a net movement in the direction indicated by the signal.
“For the first time, this gives us a general framework for analyzing the way cells move,” says Potdar.
Research Associate Junhwan Jeon, Associate Professor Alissa Weaver and Professor Vito Quaranta also participated in the study.
The research was funded by the National Cancer Institute’s Integrative Cancer Biology Program through a center grant to Vanderbilt University Medical Center. Quaranta is the grant’s principal investigator.
Adapted from materials provided by Vanderbilt University.
- 1. Alka A. Potdar, Junhwan Jeon, Alissa M. Weaver, Vito Quaranta, Peter T. Cummings. Human Mammary Epithelial Cells Exhibit a Bimodal Correlated Random Walk Pattern. PLoS ONE, 2010; 5 (3): e9636 DOI: 10.1371/journal.pone.0009636
Sims et al. Scaling laws of marine predator search behaviour. Nature, 2008; 451 (7182): 1098 DOI: 10.1038/nature06518
Fig.: The brain does not predict the unpredictable: The sight of bars apparently moving from bottom left to top right (dotted line) evokes activity in the primary visual cortex (V1). Right: in the upper part of the image, the test stimulus (a white-framed bar) is presented in such a manner that it is integrated into the motion of the white bars. In contrast, the brain does not predict the appearance of the test stimulus in the lower part of the image. This test stimulus is presented with a certain time delay, so that the motion direction appears to be interrupted. Image detail bottom left: the activity in V1 is significantly higher for the unexpected test stimulus (brown graph) than for the expected test stimulus (blue graph). (Credit: Max Planck Institute for Brain Research)
ScienceDaily.com, Mar. 22, 2010 — It turns out that there is a striking similarity between how the human brain determines what is going on in the outside world and the job of scientists. Good science involves formulating a hypothesis and testing whether this hypothesis is compatible with the scientist’s observations. Researchers in the Max Planck Institute for Brain Research in Frankfurt together with the University of Glasgow have shown that this is what the brain does as well. A study shows that it takes less effort for the brain to register predictable as compared to unpredictable images.
Alink and colleagues based this conclusion on the characteristics of responses in the primary visual cortex. It is known that the primary visual cortex is critical for vision and that responses in this brain area create a map of what we are currently looking at. Alink and colleagues, however, for the first time show that images induce smaller responses in this area when they are predictable. The implication of this finding is that the brain does not just sit and wait for visual signals to arrive. Instead, it actively tries to predict these signals and when it is right it is rewarded by being able to respond more efficiently. If it is wrong, massive responses are required to find out why it is wrong and to come up with better predictions.
One implication of this study is that when you enter the office the image of your colleague at his desk, who has the annoying trait of always being there before you, will require very little effort for your brain to register. The image of your mother in law sitting on the same chair, however, would make your brain go haywire. Not necessarily because you are not fond of this person but because this image makes it clear to your brain that it is doing a lousy job at predicting what is going to happen next and that it will have to make an effort to improve its predictions. This suggests that the brain’s main job, alike that of a scientist, is to generate hypotheses about what is going on in the outside world.
The study, published in the Journal of Neuroscience, represents a significant advance in understanding how the brain supports visual perception. An important implication of this study is that visual perception depends on an active generation of predictions. This stands in contrast to the classical view that visual perception mainly results from a more passive cascade of responses to visual signals spreading through the brain.
Further research is still required to determine whether indeed we are all carrying along a little scientist in our head. At present the idea of the scientific brain is rapidly spreading through the neuroscience community and provides a novel approach to resolving how the most complex organ of the human body works.
Adapted from materials provided by Max-Planck-Gesellschaft.
- Alink et al. Stimulus Predictability Reduces Responses in Primary Visual Cortex. Journal of Neuroscience, 2010; 30 (8): 2960 DOI: 10.1523/JNEUROSCI.3730-10.2010
This is a 3-D cell culture grown with magnetic levitation. (Credit: G. Souza/N3D Biosciences)
ScienceDaily.com, March 22, 2010 — The film “Avatar” isn’t the only 3-D blockbuster making a splash this winter. A team of scientists from Houston’s Texas Medical Center has unveiled a new technique for growing 3-D cell cultures, a technological leap from the flat petri dish that could save millions of dollars in drug-testing costs.
The research is reported in Nature Nanotechnology.
The 3-D technique is easy enough for most labs to set up immediately. It uses magnetic forces to levitate cells while they divide and grow. Compared with cell cultures grown on flat surfaces, the 3-D cell cultures tend to form tissues that more closely resemble those inside the body.
“There’s a big push right now to find ways to grow cells in 3-D because the body is 3-D, and cultures that more closely resemble native tissue are expected to provide better results for preclinical drug tests,” said study co-author Tom Killian, associate professor of physics at Rice. “If you could improve the accuracy of early drug screenings by just 10 percent, it’s estimated you could save as much as $100 million per drug.”
For cancer research, the “invisible scaffold” created by the magnetic field goes beyond its potential for producing cell cultures that are more reminiscent of real tumors, which itself would be an important advance, said co-author Wadih Arap, professor in the David H. Koch Center at The University of Texas M.D. Anderson Cancer Center.
To make cells levitate, the research team modified a combination of gold nanoparticles and engineered viral particles called “phage” that was developed in the lab of Arap and Renata Pasqualini, also of the Koch Center. This targeted “nanoshuttle” can deliver payloads to specific organs or tissues.
“A logical next step for us will be to use this additional magnetic property in targeted ways to explore possible applications in the imaging and treatment of tumors,” Arap said.
The 3-D modeling raises another interesting long-term possibility. “This is a step toward building better models of organs in the lab,” Pasqualini said.
The new technique is an example of the innovation that can result when experts come together from disparate fields. Killian studies ultracold atoms and uses finely tuned magnetic fields to manipulate them. He had been working with Rice bioengineer Robert Raphael for several years on methods to use magnetic fields to manipulate cells. So when Killian’s friend Glauco Souza, then an Odyssey Scholar studying with Arap and Pasqualini, mentioned one day that he was developing a gel that could load cancer cells with magnetic nanoparticles, it led to a new idea.
“We wondered if we might be able to use magnetic fields to manipulate the cells after my gels put magnetic nanoparticles into them,” said Souza, who left M.D. Anderson in 2009 to co-found Nano3D Biosciences (www.n3dbio.com), a startup that subsequently licensed the technology from Rice and M.D. Anderson.
The nanoparticles in this case are tiny bits of iron oxide. These are added to a gel that contains phage. When cells are added to the gel, the phage causes the particles to be absorbed into cells over a few hours. The gel is then washed away, and the nanoparticle-loaded cells are placed in a petri dish filled with a liquid that promotes cell growth and division.
In the new study, the researchers showed that by placing a coin-sized magnet atop the dish’s lid, they could lift the cells off the bottom of the dish, concentrate them and allow them to grow and divide while they were suspended in the liquid.
A key experiment was performed in collaboration with Jennifer Molina, a graduate student in the laboratory of Maria-Magdalena Georgescu, an M.D. Anderson associate professor in neuro-oncology and also a co-author, in which the technique was used on brain tumor cells called glioblastomas. The results showed that cells grown in the 3-D medium produced proteins that were similar to those produced by gliobastoma tumors in mice, while cells grown in 2-D did not show this similarity.
Souza said that Nano3D Biosciences is conducting additional tests to compare how the new method stacks up against existing methods of growing 3-D cell cultures. He said he is hopeful that it will provide results that are just as good, if not better, than longstanding techniques that use 3-D scaffolds.
Raphael, a paper co-author, associate professor in bioengineering and a member of Rice’s BioScience Research Collaborative, said, “The beauty of this method is that it allows natural cell-cell interactions to drive assembly of 3-D microtissue structures. The method is fairly simple and should be a good point of entry in 3-D cell culturing for any lab that’s interested in drug discovery, stem cell biology, regenerative medicine or biotechnology.”
Other co-authors include Daniel Stark and Jeyarama Ananta, both of Rice; Carly Levin of Nano3D Biosciences; and Michael Ozawa, Lawrence Bronk, Jami Mandelin, James Bankson and Juri Gelovani, all of M.D. Anderson.
The research was funded by M.D. Anderson’s Odyssey Scholar Program, the Department of Defense’s Breast Cancer Research Program, the National Science Foundation, the Packard Foundation, the Gillson-Longenbaugh Foundation, AngelWorks, the National Institutes of Health and the National Cancer Institute.
Adapted from materials provided by Rice University.
- 1. Glauco R. Souza, Jennifer R. Molina, Robert M. Raphael, Michael G. Ozawa, Daniel J. Stark, Carly S. Levin, Lawrence F. Bronk, Jeyarama S. Ananta, Jami Mandelin, Maria-Magdalena Georgescu, James A. Bankson, Juri G. Gelovani, T. C. Killian, Wadih Arap & Renata Pasqualini. Three-dimensional tissue culture based on magnetic cell levitation. Nature Nanotechnology, 2010; DOI: 10.1038/nnano.2010.23
Fruit flies (Drosophila melanogaster) breeding in a test tube. (Credit: iStockphoto/Joe Pogliano)
ScienceDaily.com, March 23, 2010 — Scientists at the University of California, San Diego School of Medicine, have identified a protein called Sestrin that serves as a natural inhibitor of aging and age-related pathologies in fruit flies. They also showed that Sestrin, whose structure and biochemical function are conserved between flies and humans, is needed for regulation of a signaling pathway that is the central controller of aging and metabolism.
The work, led by Michael Karin, PhD, Distinguished Professor of Pharmacology in UCSD’s Laboratory of Gene Regulation and Signal Transduction, is the cover story of the March 5 issue of the journal Science.
Sestrins are highly conserved small proteins that are produced in high amounts when cells experience stress. Sestrin function, however, remained puzzling until the Karin group found that these proteins function as activators of AMP-dependent protein kinase (AMPK), and inhibitors of the Target of Rapamycin (TOR). AMPK and TOR are two protein kinases that serve as key components of a signaling pathway shown to be the central regulator of aging and metabolism in a variety of model organisms, including the worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster and mammals.
AMPK is activated in response to caloric restriction, a condition that slows down aging, whereas TOR is activated in response to over-nutrition, a condition that accelerates aging. Activation of AMPK inhibits TOR, and drugs that activate AMPK or inhibit TOR can delay aging in several different model organisms including mammals. But how the body keeps the activity of these two protein kinases in balance to prevent premature aging was unknown. Additionally, the presence of three different genes encoding Sestrins in mammals made it difficult to identify their exact physiological function in live animals.
The new study took advantage of the finding that the fruit fly Drosophila, whose AMPK-TOR signaling pathway functions in the same manner as its mammalian equivalent, contains a single Sestrin gene. Using a variety of genetic techniques, first author Jun Hee Lee inactivated the Sestrin gene of Drosophila and found that although Sestrin-deficient flies do not exhibit any developmental abnormalities, they suffer from under-activation of AMPK and over-activation of TOR — confirming that Sestrin is needed for keeping this pathway in check. Most importantly, the biochemical imbalance incurred by loss of Sestrin expression resulted in several age-related pathologies.
“Strikingly, the pathologies caused by the Sestrin deficiency included accumulation of triglycerides, cardiac arrhythmia and muscle degeneration that occurred in rather young flies,” said Karin. “These pathologies are amazingly similar to the major disorders of overweight, heart failure and muscle loss that accompany aging in humans.”
Lee and colleagues at UC San Diego and the Sanford-Burnham Institute in La Jolla, California, went on to demonstrate that feeding flies with drugs that either activate AMPK or inhibit TOR conferred protection against most of these early aging, degenerative symptoms. The researchers also found that over-activation of TOR is likely to accelerate aging of heart and skeletal muscles by disrupting an important “quality control” process called autophagy. Autophagy allows cells to rid themselves of and replace damaged mitochondria, the little power plants that provide all cells, especially muscles, with energy. However, when mitochondria get old, they produce high concentrations of reactive oxygen species (ROS), or free radicals, that can lead to tissue damage.
Karin explained that the process of autophagy — which counteracts aging — allows the replacement of “old” and defective mitochondria with “brand new” mitochondria. Sestrin-deficient flies, however, were found to exhibit accumulation of damaged mitochondria and ROS several days prior to the detection of muscle degeneration. Feeding these flies vitamin E, an antioxidant which neutralizes free radicals, prevented premature muscle degeneration and heart failure.
In future work, the Karin group plans to examine whether the mammalian Sestrins also control aging and metabolism, and whether defects in proper Sestrin expression will provide the explanation to some of the currently unexplainable degenerative diseases associated with old age.
“Maybe one day we will be able to use Sestrin analogs to prevent much of the tissue failure associated with aging, as well as treat a number of degenerative diseases, whose incidence goes up with old age, including sarcopenia and Alzheimer’s disease,” said Karin.
Additional contributors to the study — a collaboration between three laboratories at UC San Diego School of Medicine, UCSD Division of Biology and the Sanford-Burnham Institute — are Andrei V. Budanov, Eek Joong Park, Ryan Birse, Teddy E. Kim, Guy A. Perkins, Karen Ocorr, Mark H. Ellisman, Rolf Bodmer and Ethan Bier.
The research was funded by the National Institutes of Health, the Superfund Basic Research Program and American Cancer Society.
- 1. Jun Hee Lee, Andrei V. Budanov, Eek Joong Park, Ryan Birse, Teddy E. Kim, Guy A. Perkins, Karen Ocorr, Mark H. Ellisman, Rolf Bodmer, Ethan Bier, and Michael Karin. Sestrin as a Feedback Inhibitor of TOR That Prevents Age-Related Pathologies. Science, 2010: 327 (5970): 1223-1228 DOI: 10.1126/science.1182228
People are given an oral cancer screening at a free dental clinic in Brighton, Colorado in 2009. Despite huge strides in treatment over the past four decades, cancer remains the second leading cause of death in the United States, claiming the lives of 560,000 people last year, a report in a special edition of the Journal of the American Medical Association (JAMA) has said.
GoogleNews.com, March 22, 2010 – Despite huge strides in treatment over the past four decades, cancer remains the second leading cause of death in the United States, claiming the lives of 560,000 people last year, a report said Tuesday.
The report in a special edition of the Journal of the American Medical Association (JAMA) said the work of doctors and scientists has slashed the US death rate by nearly 16 percent.
But cancer still struck 1.5 million people last year and killed 560,000, making it the second leading cause of death and an enduring medical challenge.
Preventive campaigns, such as drives to get Americans to quit smoking and early screening for breast, cervical and colon cancer, have led to a nearly one percent annual drop in the rate of new diagnoses between 1999 and 2006, the report in a special cancer-themed issue of JAMA said.
“Remarkable progress” has been made in treating childhood and other cancers, including testicular, breast, prostate and colorectal cancer, the report’s authors, Susan Gapstur and Michael Thun of the American Cancer Society, wrote.
But while some battles have been won, others were still raging. Other types of cancer — pancreatic, liver, ovarian, lung and brain — remain “highly lethal and non-responsive to current therapies,” the report said.
And as life expectancy has increased, the risk of being diagnosed with cancer has risen, too: nearly half of men and a third of women will be diagnosed during their lifetime with cancer.
Meanwhile, a separate article released ahead of publication in next week’s Archives of Internal Medicine to coincide with JAMA’s special issue, said the media focused too much on the battles won in the war against cancer and not enough on failures.
“Newspaper and magazine reports about cancer appear more likely to discuss aggressive treatment and survival than death, treatment failure or adverse events, and almost none mention end-of-life palliative or hospice care,” said the report.
Of the one in two men and one in three women who will be diagnosed with cancer in their lifetime, around half will die of cancer or related complications, it said.
And yet, only 7.6 percent of more than 400 cancer news reports published between 2005 and 2007 analyzed for the report, were about people who were dying or had died of cancer.
More than four times as many stories were upbeat accounts of cancer survivors or people who had been cured of cancer, according to researchers from the University of Pennsylvania who analyzed news reports in eight large US newspapers and five national magazines.
“It is surprising that few articles discuss death and dying considering that half of all patients diagnosed as having cancer will not survive,” the study’s authors wrote.
Gapstur and Thun said progress in the fight against cancer is complicated by the “phenomenal biological complexity of cancer in its various forms.”
Cancer is, in fact, a collection of more than 100 diseases with different prognoses, clinical features, and susceptibility to treatment. Each form of cancer is able to, and often does, change rapidly and become resistant to whatever treatment is being thrown at it.
Aerobic bacteria, Staphylococcus aureus, cultured on an agar plate for drug sensitivity test in an anaerobic environment. The toxin produced by Staphylococcus aureus causes the illness “staphylococcal intoxication”. Symptoms of this intoxication include nausea, vomiting, and diarrhea. Gram-Positive Bacterial Infections, Staphylococcal Infections. Photo from CDC
GoogleNews.com, March 22, 2010 – Scientists from the McGowan Institute for Regenerative Medicine, US, have synthesized a single, multifunctional polymer material that can decontaminate both biological and chemical toxins.
“Our lab applies biological principles to create materials that can do many things, just like our skin protects us from both rain and sun,” said senior investigator Alan Russell, University Professor of Surgery, University of Pittsburgh School of Medicine, and director, McGowan Institute.
“Typically, labs engineer products that are designed to serve only one narrow function,” he added.
Those conventional approaches might not provide the best responses for weapons of mass destruction, which could be biological, such as smallpox virus, or chemical, such as the nerve agent sarin, he noted.
Terrorists aren’t going to announce what kind of threat they unleash in an attack.
“That uncertainty calls for a single broad-spectrum decontamination material that can rapidly neutralize both kinds of threats and is easily delivered or administered, and it must not damage the environment where it is applied,” Dr. Russell said.
“Much work has gone into developing ways to thwart either germ or chemical weapons, and now we’re combining some of them into one countermeasure,” he added.
He and his team have devised a polyurethane fiber mesh containing enzymes that lead to the production of bromine or iodine, which kill bacteria, as well as chemicals that generate compounds that detoxify organophosphate nerve agents.
“This mesh could be developed into sponges, coatings or liquid sprays, and it could be used internally or as a wound dressing that is capable of killing bacteria, viruses and spores,” said lead investigator Gabi Amitai of the McGowan Institute and the Israel Institute for Biological Research.
“The antibacterial and antitoxin activities do not interfere with each other, and actually can work synergistically,” he added.
In their experiments, the material fended off Staph aureus and E. coli, which represent different classes of bacteria.
After 24 hours, it restored 70 percent of the activity of acetylcholinesterase, an enzyme that is inhibited by nerve agents leading to fatal dysfunction of an essential neurotransmitter.
The researchers continue to develop alternate decontamination strategies to address chemical and biologic weapons.
This is a scanning electron micrograph depicting Gram-positive Staphylococcus aureus bacteria. S. aureus, often referred to simply as “staph”, are bacteria commonly carried on the skin or in the nose of healthy people. Staph bacteria are one of the most common causes of skin infections in the United States. Gram-Positive Bacteria. Photo from CDC
This scanning electron micrograph depicts a grouping of methicillin resistant Staphylococcus aureus (MRSA) bacteria. These S. aureus bacteria are methicillin-resistant, and are from one of the first isolates in the U.S. that showed increased resistance to vancomycin as well. Note the increase in cell wall material seen as clumps on the organisms’ surface. Gram-Positive Bacteria. Photo from CDC