New theory uncovers cancer’s deep evolutionary roots / Cancer is realated to embryo development

Contact: Skip Derra skip.derra@asu.edu 480-965-4823 Arizona State University

 

Tracing cancer back to the dawn of multicellularity could explain its mysterious properties and transform therapy

TEMPE, Ariz. — A new way to look at cancer — by tracing its deep evolutionary roots to the dawn of multicellularity more than a billion years ago — has been proposed by Paul Davies of Arizona State University’s Beyond Center for Fundamental Concepts in Science in collaboration with Charles Lineweaver of the Australian National University. If their theory is correct, it promises to transform the approach to cancer therapy, and to link the origin of cancer to the origin of life and the developmental processes of embryos.

Davies and Lineweaver are both theoretical physicists and cosmologists with experience in the field of astrobiology — the search for life beyond Earth. They turned to cancer research only recently, in part because of the creation at Arizona State University of the Center for the Convergence of Physical Science and Cancer Biology. The Center is one of twelve established by the National Cancer Institute to encourage physical scientists to lend their insights into tackling cancer.

The new theory challenges the orthodox view that cancer develops anew in each host by a series of chance mutational accidents. Davies and Lineweaver claim that cancer is actually an organized and systematic response to some sort of stress or physical challenge. It might be triggered by a random accident, they say, but thereafter it more or less predictably unfolds.

Their view of cancer is outlined in the article “Exposing cancer’s deep evolutionary roots,” written by Davies. It appears in a special July issue of Physics World devoted to the physics of cancer.

“We envisage cancer as the execution of an ancient program pre-loaded into the genomes of all cells,” says Davies, an Arizona State University Regents Professor. “It is rather like Windows defaulting to ‘safe mode’ after suffering an insult of some sort.” As such, he describes cancer as a throwback to an ancestral phenotype.

The new theory predicts that as cancer progresses through more and more malignant stages, it will express genes that are more deeply conserved among multicellular organisms, and so are in some sense more ancient. Davies and Lineweaver are currently testing this prediction by comparing gene expression data from cancer biopsies with phylogenetic trees going back 1.6 billion years, with the help of Luis Cisneros, a postdoctoral researcher with Arizona State University’s Beyond Center.

But if this is the case, then why hasn’t evolution eliminated the ancient cancer subroutine?

“Because it fulfills absolutely crucial functions during the early stages of embryo development,” Davies explains. “Genes that are active in the embryo and normally dormant thereafter are found to be switched back on in cancer. These same genes are the ‘ancient’ ones, deep in the tree of multicellular life.”

The link with embryo development has been known to cancer biologists for a long time, says Davies, but the significance of this fact is rarely appreciated. If the new theory is correct, researchers should find that the more malignant stages of cancer will re-express genes from the earliest stages of embryogenesis. Davies adds that there is already some evidence for this in several experimental studies, including recent research at Harvard University and the Albert Einstein College of Medicine in New York.

“As cancer progresses through its various stages within a single organism, it should be like running the evolutionary and developmental arrows of time backward at high speed,” says Davies.

This could provide clues to future treatments. For example, when life took the momentous step from single cells to multicellular assemblages, Earth had low levels of oxygen. Sure enough, cancer reverts to an ancient form of metabolism called fermentation, which can supply energy with little need for oxygen, although it requires lots of sugar.

Davies and Lineweaver predict that if cancer cells are saturated with oxygen but deprived of sugar, they will become more stressed than healthy cells, slowing them down or even killing them. ASU’s Center for the Convergence of Physical Science and Cancer Biology, of which Davies is principal investigator, is planning a workshop in November to examine the clinical evidence for this.

“It is clear that some radically new thinking is needed,” Davies states. “Like aging, cancer seems to be a deeply embedded part of the life process. Also like aging, cancer generally cannot be cured but its effects can certainly be mitigated, for example, by delaying onset and extending periods of dormancy. But we will learn to do this effectively only when we better understand cancer, including its place in the great sweep of evolutionary history.”

Clues about autism may come from the gut

Contact: Joseph Caspermeyer Joseph.Caspermeyer@asu.edu Arizona State University

Bacterial flora inhabiting the human gut have become one of the hottest topics in biological research. Implicated in a range of important activities including digestion, fine-tuning body weight, regulating immune response, and producing neurotransmitters affect that brain and behavior, these tiny workers form diverse communities. Hundreds of species inhabit the gut, and although most are beneficial, some can be very dangerous.

In new research appearing in the journal PLOS ONE, a team led by Rosa Krajmalnik-Brown, a researcher at Arizona State University’s Biodesign Institute, present the first comprehensive bacterial analysis focusing on commensal or beneficial bacteria in children with autism spectrum disorder (ASD).

After publishing earlier research exploring crucial links between intestinal microflora and gastric bypass, Krajmlanik-Brown convinced James Adams— director of the ASU Autism/Asperger’s Research Program—that similar high throughput techniques could be used to mine the microbiome of patients with autism. (Previously, Adams had been studying the relationship between the gut microbiome and autism using traditional culturing techniques.)

“One of the reasons we started addressing this topic is the fact that autistic children  have a lot of GI problems that can last into adulthood,” Krajmalnik-Brown  says. “Studies have shown that when we manage these problems, their behavior improves dramatically.”

Following up on these tantalizing hints, the group hypothesized the existence of distinctive features in the intestinal microflora found in autistic subjects compared to typical children. The current study confirmed these suspicions, and found that children with autism had significantly fewer types of gut bacteria, probably making them more vulnerable to pathogenic bacteria.  Autistic subjects also had significantly lower amounts of three critical bacteria, Prevotella, Coprococcus, and Veillonellaceae.

Krajmalnik-Brown, along with the paper’s lead authors Dae-Wook Kang and Jin Gyoon Park, suggest that knowledge gleaned through such research may ultimately be used both as a quantitative e diagnostic tool to pinpoint autism and as a guide to developing effective treatments for ASD-associated GI problems.  The work also offers hope for new prevention and treatment methods for ASD itself, which has been on a mysterious and rapid ascent around the world.

A disquieting puzzle

Autism is defined as a spectrum disorder, due to the broad range of symptoms involved and the influence of both genetic and environmental factors, features often confounding efforts at accurate diagnosis. The diseases’ prevalence in children exceeds juvenile diabetes, childhood cancer and pediatric AIDS combined.

Controversy surrounds the apparent explosive rise in autism cases. Heightened awareness of autism spectrum disorders and more diligent efforts at diagnosis must account for some of the increase, yet many researchers believe a genuine epidemic is occurring. In addition to hereditary components, Western-style diets and overuse of antibiotics at an early age may be contributing to the problem by lowering the diversity of the gut microflora.

In terms of severe developmental ailments affecting children and young adults, autism is one of the most common, striking about 1 in 50 children. The disorder—often pitiless and perplexing—is characterized by an array of physical and behavioral symptoms including anxiety, depression, extreme rigidity, poor social functioning and an overall lack of independence.

To date, studies of the gut microbiome in autistic subjects have focused primarily on pathogenic bacteria, some of which have been implicated in alterations to brain function.  One example involves gram-negative bacteria containing lipopolysaccharides in their cell walls, which can induce inflammation of the brain and lead to the accumulation of high levels of mercury in the cerebrum.

A new approach

Krajmalnik-Brown and lead author Dae-Wook Kang are researchers in the Biodesign Institute’s Swette Center for Environmental Biotechnology, which is devoted to the use of microbial communities for the benefit of human and environmental health. Their new study is the first to approach autism from a different angle, by examining the possible role of so-called commensal or beneficial bacteria.

Up to a quadrillion (1014) bacteria inhabit the human intestine, contributing to digestion, producing vitamins and promoting GI health. Genes associated with human intestinal flora are 100 times as plentiful as the body’s human genes, forming what some have referred to as a second genome. Various environmental factors can destabilize the natural microbiome of the gut, including antibiotics and specific diets.

In the current study, a cohort of 20 healthy and 20 autistic subjects between 3 and 16 years of age were selected and their gut microflora from fecal samples analyzed by means of a technique known as pyrosequencing. Pyrosequencing is a high-throughput method, allowing many DNA samples to be combined as well as many sequences per sample to be analyzed.

Lower diversity of gut microbes was positively correlated with the presence of autistic symptoms in the study. The authors stress that bacterial richness and diversity are essential for maintaining a robust and adaptable bacterial community capable of fighting off environmental challenges. “We believe that a diverse gut is a healthy gut,” Krajmalnik-Brown says.

The new study detected decreased microbial diversity in the 20 autistic subjects whose fecal samples were analyzed. Specifically, three bacterial genera—Prevotella, Coprococcus and Veillonellaceae—were diminished in subjects with autism, when compared with samples from normal children. (Surprisingly, these microbial changes did not seem directly correlated with the severity of GI symptoms.)

The three genera represent important groups of carbohydrate-degrading and/or fermenting microbes.  Such bacteria could be critical for healthy microbial-gut interactions or play a supportive role for  a wide network of different microorganisms in the gut. The latter would explain the decreased diversity observed in autistic samples.

Bacteria: in sickness and in health

Among the fully classified genera in the study, Prevotella was the most conspicuously reduced in autistic subjects. Prevotella is believed to play a key role in the composition of the human gut microbiome. For this reason, the group undertook a sub-genus investigation of autistic subjects. They found that a species known as Prevotella copri occurred only in very low levels in the autistic samples. The species is a common component in normal children exhibiting more diverse and robust microbial communities.

“We think of Prevotella as a healthy, good thing to have,” Krajmalnik-Brown notes. (Michael Polan’s recent New York Times Magazine story on the microbiome points to the fact that he is proud that his gut microbiome is rich in Prevotella regarding it as a possible sign of a healthy non-Western diet.)

Jin Gyoon Park (the other lead author),  who works in the Virginia G. Piper Center for Personalized Diagnostics, under Joshua LaBaer’s direction, conducted a rigorous bioinformatic and statistical analysis of the intestinal microflora. He believes that the microbiome can be mined in future work to find diagnostic biomarkers for autism and many other diseases. Quantitative diagnoses of this sort have so far been lacking for autism, a disease for which subjective behavior indices are typically used to identify the disorder.

In describing the next steps for the research group, Kang and Park point to more detailed, gene-level analyses aimed at probing bacterial function and further illuminating relationships between human health and the complexities of the microbiome.  Additionally, the group will use the current results as a guide for new treatment studies for autism aimed at modifying bacterial composition in the gut.

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A new, interdisciplinary consortium (Autism Microbiome Consortium) has been formed to investigate the underpinings of autism and the gut microbiome, bringing together the combined skills of neurologists, psychiatrists, neuroimmunologists, epidemiologists, pediatricians, geneticists, biochemists, microbiologists and others. In addition to Rosa Krajmalnik-Brown and James Adams, the group consists of:

Jack Gilbert (University of Chicago), Catherine Lozupone (University of Colorado), Rob Knight (University of Colorado and HHMI). Mady Hornig (Columbia University), Sarkis Mazmanian (California Institute of Technology), Tanya Murphy (University of South Florida), , Paul Patterson (California Institute of Technology), John Alverdy (University of Chicago), Janet Jansson (Lawrence Berkeley Lab), KImberly Johnson (University of Colorado).

Written by: Richard Harth Science Writer: Biodesign Institute richard.harth@asu.edu

Cyborg Roaches, Glow-in-the-Dark Fish, and Other Biotechnology Beasts

Cyborg Roaches, Glow-in-the-Dark Fish, and Other Biotechnology Beasts
By Emily Anthes
Posted Monday, Feb. 25, 2013, at 10:34 AM
Slate.com
Cyborg Beetle 4-MM

A remote-controlled flying flower beetle. Photo courtesy Michel Maharbiz.

This article arises from Future Tense, a partnership of Slate, the New America Foundation, and Arizona State University. On Feb. 28-March 2, Future Tense will be taking part in Emerge, an annual conference on ASU’s Tempe campus about what the future holds for humans. This year’s theme: the future of truth. Visit the Emerge website to learn more and to get your ticket.

I have seen the future of animals and it is glowing. Literally.

Three years ago, I set out to explore the world of animal biotechnology, to see just how scientists were using advances in genetics, electronics, and materials science to totally re-engineer and re-invent animal bodies.

I discovered that researchers were genetically engineering cats—and monkeys and mice—that glowed electric green under a black light. They were cloning pets, livestock, and endangered species. And they were using neural implants to create remote-controlled, cyborg critters.

Mr. Green Genes 2-ACRES

Mr. Green Genes under a black light. Photo courtesy Audubon Nature Institute.

That wasn’t entirely shocking; biotechnology moves fast, and scientists are capable of dreaming up, and then achieving, remarkable things. What did take me by surprise, however, was how many of these sci-fi, futuristic critters have already made their way out of the laboratory and into our farms, fields, and families.

For instance, as I describe in my new book Frankenstein’s Cat, biologists have spent a lot of time playing around with fluorescence genes. These genes, which are naturally present in a variety of marine organisms—including certain species of jellyfish, sea anemones, and coral—code for proteins that give off dazzling, Dayglo colors in certain lighting conditions. For years, scientists have been experimenting with transferring these fluorescence genes into all sorts of critters, creating neon cats, dogs, pigs, and more. Such creatures can help scientists unravel important research questions. By linking a fluorescence gene to a piece of a rat’s native DNA, for instance, biologists can learn precisely when that rat gene turns on—all they have to do is wait for the rat to glow.

Now, even us non-scientists can own one of these strange creatures. In 2004, a company called Yorktown Technologies began selling GloFish in pet stores across the country. The fish are zebrafish—tropical freshwater swimmers that are normally simply black and white—that carry fluorescence genes from sea coral and sea anemones. As a result, the fish come in a radiant rainbow of colors, glowing red, orange, green, blue, or purple under an ultraviolet light. The fish are widely available—they’re sold at PetCo, as you might expect, but also at WalMart—and cost $5 or $6 a piece, which means that nearly anyone who wants to can bring home a high-tech pet. Rather than being used for practical purposes, like evaluating the effectiveness of new genetic engineering techniques, GloFish are merely intended to be fun.  (And they are. I bought a few of my own GloFish a few years ago. They have since gone on to the great aquarium in the sky, but they were delightful while they lasted.)

GloFish 3

GloFish, America’s first transgenic pets. Photo courtesy Yorktown Technologies

Those with more money to burn—say, $100,000—can acquire a clone of a beloved animal. A handful of these DNA doubles already live among us, including Little Nicky, a clone of a Maine Coon cat named Nicky, and Lancelot Encore, a duplicate of a yellow Lab named (what else?) Lancelot. And every year, hundreds of cloned farm animals—mostly cows—are born in the United States, to relatively little fanfare. Though cloning is still an experimental technique, it’s been embraced by ranchers and farmers eager to make genetic doubles of their best animals. (The animals are likely not in the food supply—the USDA has issued a voluntary moratorium, requesting that those who own cloned livestock keep them away from our dinner tables—and cloned cows are simply too valuable to be slaughtered for meat. So far, the cattle are being mainly used as breeding stock, propagating their superlative genes, and are being entered into prestigious livestock competitions.) Clones could even be coming to the Olympics; last year, the international body that governs equestrian competitions lifted its ban on cloned equines.

Cloning also provides the opportunity to make healthier livestock—researchers at Texas A&M, for instance, cloned a Black Angus bull that had a natural resistance to Brucellosis, an infectious bacterial disease common among cattle. The clone, which students dubbed “Bruce,” is resistant to Brucellosis, too, and could potentially be used to breed a whole new line of disease-free cattle.

Bruce

A cloned Angus bull that’s resistant to Brucellosis, a common cattle disease. Photo by Emily Anthes

Thanks to the work of a few pioneering veterinarians, when our pets’ bodies begin to fail, we can give them bionic upgrades. Consider Coal, an American bulldog who developed a tumor in his front paw. Many dogs with similar afflictions simply have their legs amputated and learn to adjust to life as three-limbed canines. But Coal was arthritic and really benefitted from the support of a fourth leg, so a British veterinarian named Noel Fitzpatrick built him a bionic one. Fitzpatrick gave Coal an “osseointegrated” prosthesis, permanently implanting one end of a titanium rod inside what remained of Coal’s leg bone. The other end of the rod protruded from the dog’s stump and could be affixed to a removable artificial paw.

Coal-FR copy

A bulldog with an osseointegrated prosthetic leg. Photo courtesy Fitzpatrick Referrals.

Coal did well on his new leg, and he wasn’t alone. Fitzpatrick has given some two dozen animals the same kind of osseointegrated prosthesis, and an American vet has built similar devices for two cats and six dogs. Prosthetists have also built an artificial tail for a dolphin, a beak for a bald eagle, and legs for sandhill cranes.

Winter-WH copy

Winter the bottlenose dolphin, wearing her prosthetic tail. Photo courtesy Hanger Inc.

Even the most sci-fi of techniques are trickling out to the public. Advances in electronics have given us the ability to hijack animal bodies and brains, taking control of another creature’s movements and behaviors. Predictably, much of this work has been done in official, university labs: Engineers and neuroscientists at the University of California- Berkeley, Cornell, and the State University of New York Downstate have created remote-controlled, cyborg beetles, moths, and rats, respectively. But these sophisticated tools of mind control are also now available to the general public. A company called Backyard Brains sells a RoboRoach kit for $100; anyone who buys the kit online can make their very own steerable, cyborg cockroaches.

RoboRoach-EA

A remote-controlled cockroach. Photo by Emily Anthes.

I got the chance to test-drive one, if you will, two years ago in Woods Hole, Massachusetts, using a tiny remote control to command the bug to spin left or right. The experiment seemed pretty harmless—and it was definitely cool—but the implications of hijacking another creature’s nervous system were certainly creepy. The founders of Backyard Brains hope the RoboRoach inspires a new generation of kids to pursue neuroscience and the scientists creating other remote-controlled animals have all sorts of important civilian and military applications in mind for their cyborgs. These goals may well justify our tinkering, but if this is a road we’re going to go down, we need to start thinking through the ethical ramifications of our actions, and we need to do it soon. After all, as I picked the RoboRoach up off the sidewalk, I realized that the future of animal biotechnology was no longer some distant, abstract notion—it was sitting right in front of me, tickling the palm of my hand.

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Study finds higher levels of several toxic metals in children with autism

James Adams uatism research

James Adams, a professor of materials science and engineering, has done extensive research into autism. He directs the ASU Autism/Asperger’s Research Program. Photo: Jessica Slater/ASU

Posted February 25, 2013

In a recently published study in the journal Biological Trace Element Research, Arizona State University researchers report that children with autism had higher levels of several toxic metals in their blood and urine compared to typical children. The study involved 55 children with autism ages 5–16 years compared to 44 controls of similar age and gender.

The autism group had significantly higher levels of lead in their red blood cells (+41 percent) and significantly higher urinary levels of lead (+74 percent), thallium (+77 percent), tin (+115 percent), and tungsten (+44 percent).  Lead, thallium, tin, and tungsten are toxic metals that  can impair brain development and function, and also interfere with the normal functioning of other body organs and systems.

A statistical analysis was conducted to determine if the levels of toxic metals were associated with autism severity, using three different scales of autism severity. It was found that 38-47 percent of the variation of autism severity was associated with the level of several toxic metals, with cadmium and mercury being the most strongly associated.

In the paper about the study, the authors state “We hypothesize that reducing early exposure to toxic metals may help ameliorate symptoms of autism, and treatment to remove toxic metals may reduce symptoms of autism; these hypotheses need further exploration, as there is a growing body of research to support it.”

The study was led by James Adams, a President’s Professor in the School for Engineering of Matter, Transport and Energy, one of ASU’s Ira A. Fulton Schools of Engineering.  He directs the ASU Autism/Asperger’s Research Program.

Adams previously published a study on the use of DMSA, an FDA-approved medication for removing toxic metals.  The open-label study found that DMSA was generally safe and effective at removing some toxic metals. It also found that DMSA therapy improved some symptoms of autism. The biggest improvement was for children with the highest levels of toxic metals in their urine.

Overall, children with autism have higher average levels of several toxic metals, and levels of several toxic metals are strongly associated with variations in the severity of autism for all three of the autism severity scales investigated.

The study was funded by the Autism Research Institute and the Legacy Foundation.

Media Contact: Joe Kullman, joe.kullman@asu.edu (480) 965-8122 Ira A. Fulton Schools of Engineering

New DNA vaccine technology poised to deliver safe and cost-effective disease protection

 

Contact: Richard Harth
richard.harth@asu.edu
Arizona State University

New and increasingly sophisticated vaccines are taking aim at a broad range of disease-causing pathogens, targeting them with greater effectiveness at lower cost and with improved measures to ensure safety.

To advance this quest, a research team led by Roy Curtiss, director of the Center for Infectious Diseases and Vaccinology, and Wei Kong, a research assistant professor, at Arizona State University’s Biodesign Institute have taken a dramatic step forward, revealing the design of a universal platform for delivering highly potent DNA vaccines, by employing a cleverly re-engineered bacterium to speed delivery to host cells in the vaccine recipient.

“The technology that we’re describing in this paper can be used to develop a vaccine against any virus, any parasite, any fungus, whereas this was never possible before the development of recombinant attenuated bacterial strains like those produced in our lab,” Curtiss says.

The experimental vaccine described in the new research demonstrated complete protection from influenza in mice, but Wei Kong, the leading author of the new study stresses that the innovative technique could be applied to the rapid manufacture of effective vaccines against virtually any infectious invader at dramatically reduced cost and without risk to either those vaccinated or the wider public.

“By delivering the DNA vaccine using a recombinant attenuated bacterium, we can get 10,000-100,000 doses per liter of culture,” Kong says, an improvement of 3-4 orders of magnitude over use of the naked plasmid DNA, which must be painstakingly isolated from bacteria before injection.

The group’s research results appear in the online Early Edition (EE) of the Proceedings of the National Academy of Sciences, the week of November 5, 2012.

 

Designing a vaccine that is both safe and effective presents a kind of Catch-22 for researchers. Live pathogenic strains typically generate a robust immune response, mimicking natural infection, but many challenges exist in terms of ensuring such strains do not cause illness or escape into the environment, where they have the potential to remain viable. Killed pathogen strains or vaccines produced from pathogen subunits sacrifice some of their immunogenic effectiveness for enhanced safety, and may require subsequent booster doses to ensure continued effectiveness.

The Curtiss team has worked to combine safety and effectiveness in orally administered vaccines that can be produced at a fraction of the cost of traditional methods. To do this, they have pioneered techniques using Salmonella—the notorious agent associated with food-borne illness—as a cargo vessel to deliver a suite of disease antigens to the recipient. The result has been the development and ongoing refinement of so-called RASVs (for recombinant attenuated Salmonella vaccines), capable of provoking an intense, system-wide immune response and conferring effective immunity.

One of the key innovations developed earlier by Wei Kong and other members of the Curtiss group, is a specialized Salmonella strain that can be timed to self-destruct in the body once it has carried out its immunization duties. To create this strain, the researchers modified the bacterium in such a way that it can only survive on a non-naturally occurring form of sugar. Once the Salmonella cells exhaust their store of specialized sugar, supplied to them as part of the vaccine, they are unable to maintain the integrity of their cell walls and they essentially implode. “This crucial safety feature ensures that Salmonella are unable to persist as living organisms to survive if excreted into the environment,” says Kong.

This self-destruct feature can be fine-tuned so that the bacteria fully colonize host cells, provoking a strong response from both humoral and cell-mediated arms of the immune system. Inside host tissues, recombinant Salmonella are able to synthesize protective antigens, releasing their contents when they become unstable and lyse into the intracellular fluid or cytosol.

The group demonstrated the effectiveness of this delayed-lysis bacteria in vaccine experiments with a variety of pathogens, including influenza and mycobacteria (causative agent of tuberculosis) and an RASV vaccine developed in the Curtiss lab against infant pneumonia is currently in FDA Phase I clinical trials. This earlier work focused on producing protective protein antigens in a bacterium, which would subsequently release a bolus of these antigens when the bacterial cell lysed within host cells and tissues.

In the latest research, the group sought to turn a delayed-lysis Salmonella strain into a universal DNA vaccine delivery vehicle. DNA vaccines stimulate cellular and humoral immune responses to protein antigens through the direct introduction of genetic material, prompting host cells to manufacture specific gene products. This is a crucial advance as it allows for the production of antigens that undergo host cell modification through the addition carbohydrates—a process known as glycosylation. Such modified antigens, which occur in a broad range of pathogenic viruses, fungi and parasites require synthesis by host cells, rather than by the attenuated bacteria.

“Here, we were able to deliver a vaccine whose DNA sequence induces the immunized individual to make the protective glycoprotein the way you would during a viral infection,” Curtiss says. Previous efforts to achieve this advance for delivery of DNA vacines by bacteria date to 1995, but only now has such work come to fruition.

A number of key modifications to the delayed-lysis RASV were required for this feat, and the Kong and Curtiss team has worked intensively over the past 5 years to achieve them. A hyperinvasive form of Salmonella was constructed through recombinant DNA methods in order to maximize the vaccine vector’s ability to invade host cells and become internalized.

Following host cell uptake, Salmonella are encased in a membrane-bound endosome known as the Salmonella Containing Vacuole. The RASV was further modified to permit escape from the endosome so that the mature bacterium could spew its immunogenic contents into the host cell’s cytosol.

Finally, further revisions to the Salmonella strain were applied to diminish the pathogen’s ability to cause host cell death, which would prevent the DNA vaccine from migrating to the host cell nucleus to induce the synthesis of protective antigens necessary for the immune response.

The authors note that their orally-administered RASV is markedly superior to earlier efforts which introduced DNA vaccines by means of intramuscular injection or gene gun. These methods fail to deliver the vaccine to both mucosal tissues and certain internal lymphoid tissues, vital to a sustained, protective immunity. “We can protect mice to doses of influenza that would be lethal were they not effectively immunized,” Curtiss says, adding that “RASV safety has been established in mice just two hours old as well as in pregnant and immunodeficient mice”.

Influenza spreads around the world in seasonal epidemics, resulting in about three to five million yearly cases of severe illness and about 250,000 to 500,000 yearly deaths, rising to millions in some pandemic years. Current manufacture of influenza vaccines requires use of chick embryos or cell culture methods. Global capacity is limited, making sufficient vaccine to immunize everyone impossible. Adding to concerns about managing future naturally occurring influenza epidemics is the potential for bioterrorists to produce weaponized influenza strains created using plasmid-based reverse genetics systems. “Increasing the speed of producing a matching vaccine is key in the context of response to an influenza epidemic,” Kong says.

The ability to rapidly engineer and scale up effective vaccines for influenza and other potentially lethal pathogens will require innovative approaches to vaccine design, manufacture and application. The universal DNA vaccine platform outlined in the new study represents an important advance.

“The vast majority of viruses including influenza, measles, mumps and HIV all have glycosylated proteins. You could never deliver protective immunity using a bacterium to produce those protein antigens,” Curtiss says. “But now we have the opportunity to produce vaccines against such pathogens,” Kong says. Further, the technique permits large quantities of DNA vaccine to be produced rapidly at low cost, freeze-dried and stockpiled to be used when needed.

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Dr Roy Curtiss is also a professor in the College of Liberal Arts and Sciences, School of Life Sciences

Written by: Richard Harth
Science Writer: The Biodesign Institute
richard.harth@asu.edu

Sources:
Roy Curtiss, (480) 727-0445
Wei Kong, (480) 727-9591

The Next Wave in U.S. Robotic War: Drones on Their Own : Autonomous Robotic Weapons

Sep. 28, 2012 – 12:04PM   |  By AGENCE FRANCE-PRESSE

WASHINGTON — The U.S. military’s current fleet of drones will soon be overtaken by a new wave of robots that will be faster, stealthier and smarter — operating virtually without human intervention, experts say.

The Pentagon is investing heavily in “autonomy” for robotic weapons, with researchers anticipating squadrons of drones in the air, land or sea that would work in tandem with manned machines — often with a minimum of supervision.

“Before they were blind, deaf and dumb. Now we’re beginning to make them to see, hear and sense,” Mark Maybury, chief scientist for the U.S. Air Force, told AFP.

Unmanned aircraft are now overseen by “pilots” on the ground but as the drones become more sophisticated, the role of remote operators will be more hands-off.

Instead of being “in the loop,” humans will be “on the loop,” said Maybury, explaining that operators will be able to “dial in” when needed to give a drone direction for a specific task.

“We’re moving into more and more autonomous systems. That’s an evolutionary arc,” said Peter Singer, an expert on robotic weapons and author of “Wired for War.”

“So the role moves from being sort of the operator from afar, to more like the supervisor or manager, and a manager giving more and more of a leash, more and more independence,” he said.

Despite the dramatic advances in technology, the American military insists humans will remain in control when it comes to using lethal force.

But the next generation of increasingly capable drones will stretch man’s capacity to control robots in battle, generating unprecedented moral and legal quandaries.

“These (technological) responses that are driven by science, politics and battlefield necessity get you into areas where the lawyers just aren’t ready for it yet,” Singer told AFP.

Over the next decade, changes in computing power will enable teams of hi-tech drones to operate virtually on their own, or as “robotic wingmen” to piloted aircraft, said Werner Dahm, the Air Force’s former top scientist.

At a testing range in the Arizona desert, Apache helicopters are flying together with unmanned choppers in experiments the Pentagon believes will serve as an eventual model for future warfare.

“We’re not far away from having a single piloted Apache or other helicopter system and a larger number of unmanned systems that fly with that,” said Dahm, a professor of mechanical and aerospace engineering at Arizona State University.

“These require very high levels of machine reasoning. We’re much closer to that than most people realize,” Dahm told AFP.

The new technology has turned the U.S. Air Force’s doctrine upside down. For decades, the military trained pilots to face an enemy “alone and unafraid,” flying deep into hostile territory to strike at a target and then return home.

Now the Air Force is planning for scenarios in which different tasks would be divided up among manned and unmanned “systems,” with drones jamming enemy air defenses, tracking targets and assessing bomb damage, while piloted warplanes oversee the launching of bombs and missiles.

Instead of the slow-flying turbo-prop Predator, future drones likely will more closely resemble their manned counterparts, with a longer range, more powerful jet engines and radar-evading stealth design, which the bat-winged Sentinel drone already has pioneered.

But the biggest technical hurdle for Pentagon-funded scientists is delivering an iron-clad guarantee that the more autonomous vehicles will not make a grievous mistake with potentially catastrophic consequences.

“You have to be able to show that the system is not going to go awry — you have to disprove a negative,” Dahm said. “It’s very difficult to prove that something won’t go wrong.”

One veteran robotics scientist, Ronald Arkin, a professor at the Georgia Institute of Technology, believes that countries will inevitably deploy independent robots capable of killing an enemy without a human pushing a button.

Arkin, who has worked on US defense programs for years, argues that robotic weapons can and should be designed as “ethical” warriors, with the ability to distinguish combatants from innocent civilians.

Without emotions to cloud their judgment and anger driving their actions, the robots could wage war in a more restrained, “humane” way, in accordance with the laws of war, Arkin said.

“It is not my belief that an unmanned system will be able to be perfectly ethical in the battlefield, but I am convinced that they can perform more ethically than human soldiers are capable of,” he wrote.

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Scientists use sound waves to levitate liquids, improve pharmaceuticals

Contact: Jared Sagoff jsagoff@anl.gov 630-252-5549 DOE/Argonne National Laboratory

It’s not a magic trick and it’s not sleight of hand – scientists really are using levitation to improve the drug development process, eventually yielding more effective pharmaceuticals with fewer side effects.

Scientists at the U.S. Department of Energy’s (DOE) Argonne National Laboratory have discovered a way to use sound waves to levitate individual droplets of solutions containing different pharmaceuticals. While the connection between levitation and drug development may not be immediately apparent, a special relationship emerges at the molecular level.

At the molecular level, pharmaceutical structures fall into one of two categories: amorphous or crystalline. Amorphous drugs typically are more efficiently taken up by the body than their crystalline cousins; this is because amorphous drugs are both more highly soluble and have a higher bioavailability, suggesting that a lower dose can produce the desired effect.

“One of the biggest challenges when it comes to drug development is in reducing the amount of the drug needed to attain the therapeutic benefit, whatever it is,” said Argonne X-ray physicist Chris Benmore, who led the study.

“Most drugs on the market are crystalline – they don’t get fully absorbed by the body and thus we aren’t getting the most efficient use out of them,” added Yash Vaishnav, Argonne Senior Manager for Intellectual Property Development and Commercialization.

Getting pharmaceuticals from solution into an amorphous state, however, is no easy task. If the solution evaporates while it is in contact with part of a vessel, it is far more likely to solidify in its crystalline form.  “It’s almost as if these substances want to find a way to become crystalline,” Benmore said.

In order to avoid this problem, Benmore needed to find a way to evaporate a solution without it touching anything. Because liquids conform to the shape of their containers, this was a nearly impossible requirement — so difficult, in fact, that Benmore had to turn to an acoustic levitator, a piece of equipment originally developed for NASA to simulate microgravity conditions.

Levitation or “containerless processing” can form pristine samples that can be probed in situ with the high-energy X-ray beam at Argonne’s Advanced Photon Source. “This allows amorphization of the drug to be studied while it is being processed,” said Rick Weber, who works on the project team at the synchrotron.

The acoustic levitator uses two small speakers to generate sound waves at frequencies slightly above the audible range – roughly 22 kilohertz. When the top and bottom speakers are precisely aligned, they create two sets of sound waves that perfectly interfere with each other, setting up a phenomenon known as a standing wave.

At certain points along a standing wave, known as nodes, there is no net transfer of energy at all. Because the acoustic pressure from the sound waves is sufficient to cancel the effect of gravity, light objects are able to levitate when placed at the nodes.

Although only small quantities of a drug can currently be “amorphized” using this technique, it remains a powerful analytical tool for understanding the conditions that make for the best amorphous preparation, Vaishnav explained.

Argonne researchers have already investigated more than a dozen different pharmaceuticals, and the laboratory’s Technology Development & Commercialization Division is currently pursuing a patent for the method. Technology Development & Commercialization is also interested in partnering with the pharmaceutical industry to develop the technology further as well as to license it for commercial development.

After adapting the technology for drug research, the Argonne scientists teamed up with Professors Stephen Byrn and Lynne Taylor at the Department of Industrial and Physical Pharmacy at Purdue University and Jeffery Yarger of the Department of Chemistry and Biochemistry at Arizona State University. The group is now working on identifying which drugs the levitation instrumentation will impact most strongly.

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Argonne National Laboratory seeks solutions to pressing national problems in science and technology. The nation’s first national laboratory, Argonne conducts leading-edge basic and applied scientific research in virtually every scientific discipline. Argonne researchers work closely with researchers from hundreds of companies, universities, and federal, state and municipal agencies to help them solve their specific problems, advance America’s scientific leadership and prepare the nation for a better future. With employees from more than 60 nations, Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy’s Office of Science.

DOE’s Office of Science is the single largest supporter of basic research in the physical sciences in the United States, and is working to address some of the most pressing challenges of our time.  For more information, please visit science.energy.gov.

New salmonella-based ‘clean vaccines’ aid the fight against infectious disease:To accomplish this, a recombinant strain of Salmonella was constructed using genes from another pathogen, Francisella tularensis

* They are using genes from tularensis ” inhaling as few as 10 bacteria could be potentially deadly ” I feel uncomfortable with the Gates foundation funding support utilizing a Bioweapon strain of  Rabbit Fever?

 

New salmonella-based ‘clean vaccines’ aid the fight against infectious disease

A powerful new class of therapeutics, known as recombinant attenuated Salmonella vaccines (RASV), holds great potential in the fight against fatal diseases including hepatitis B, tuberculosis, cholera, typhoid fever, AIDS and pneumonia.

Now, Qingke Kong and his colleagues at the Biodesign Institute at Arizona State University, have developed a technique to make such vaccines safer and more effective. The group, under the direction of Dr. Roy Curtiss, chief scientist at Biodesign’s Center for Infectious Diseases and Vaccinology, demonstrated that a modified strain of Salmonella showed a five-fold reduction in virulence in mice, while preserving strong immunogenic properties.

Their findings appear in the cover story of the current issue of the Journal of Immunology.

Streptococcus pneumoniae, an aerobic bacterium, is the causative agent of diseases including community-acquired pneumonia, otitis media, meningitis, and bacteremia. It remains a leading killer—childhood pneumonia alone causing some 3 million fatalities annually, mostly in poorer countries.

Existing vaccines are inadequate for protecting vulnerable populations for several reasons. Heat stabilization and needle injection are required, which are often impractical for mass inoculation efforts in the developing world. Repeated doses are also needed to induce full immunity. Finally, the prohibitively high costs of existing vaccines often deprive those who need them most.  The problem is exacerbated by the recent emergence of antibiotic-resistant strains of pneumococcus causing the disease, highlighting the urgency of developing safe, effective, and lower-cost antipneumococcal vaccines.

One of the most promising strategies for new vaccine development is to use a given pathogen as a cargo ship to deliver key antigens from the pathogen researchers wish to vaccinate against. Salmonella, the bacterium responsible for food poisoning, has proven particularly attractive for this purpose, as Curtiss explains: “Orally-administered RASVs stimulate all three branches of the immune system stimulating mucosal, humoral, and cellular immunity that will be protective, in this case, against a majority of pneumococcal strains causing disease.”

Recombinant Salmonella is a highly versatile vector—capable of delivering disease-causing antigens originating from viruses, bacteria and parasites.  An attenuated Salmonella vaccine against pneumonia, developed in the Curtiss lab, is currently in FDA phase 1 clinical trials.

In the current research, the team describe a method aimed at retaining the immunogenicity of an anti-pneumonia RASV while reducing or eliminating unwanted side effects sometimes associated with such vaccines, including  fever and intestinal distress. “Many of the symptoms associated with reactogenic Salmonella vaccines are consistent with known reactions to lipid A, the endotoxin component of the Salmonella lipopolysaccharide (LPS),” the the major surface membrane component , Kong explained.   “In this paper, we describe a method for detoxifying the lipid A component of LPS in living cells without compromising the ability of the vaccine to stimulate a desirable immune response.”

To achieve detoxification, Salmonella was induced to produce dephosphoylated lipid A, rendering the vaccine safer, while leaving its ability to generate a profound, system-wide immune response, intact.

To accomplish this, a recombinant strain of Salmonella was constructed using genes from another pathogen, Francisella tularensis, a bacterium associated with tularemia or rabbit fever. Salmonella expressing lipid A 1-phosphatase from tularensis (lpxE) showed less virulence in mice, yet acted to inoculate the mice against subsequent infection by wild-type Salmonella.

In further experiments, the group showed that Salmonella strains could also be constructed to additionally synthesize pneumococcal surface protein A (PspA)—a key antigen responsible for generating antibodies to pneumonia. Again, the candidate RASV displayed nearly complete dephosphorylation of lipid A, thereby reducing toxicity.

Following inoculation with the new Salmonella strain, mice produced a strong antibody response to PspA and showed greatly improved immunity to wild-type Streptococcus pneumoniae, compared with those inoculated with Salmonella lacking  the PspA antigen. Tissue culture studies showing reduction of inflammatory cytokines following application of modified lipid A further buttressed the results.

Francisella LpxE was shown to effectively strip the 1-phosphate group from Salmonella‘s lipid A, without loss of the bacterium’s capacity for colonization. The research holds promise for constructing modified live attenuated Salmonella vaccine strains for humans, with dephosphoylated lipid A providing additional safety benefits.

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The research was supported by grants from the Bill and Melinda Gates Foundation and the National Institute of Health

* Reposted on Request

ASU study finds antimicrobials from personal care products in statewide survey of Minnesota’s rivers and lakes – triclosan

Highlights

  • First statewide U.S. survey finds antimicrobial compounds present in sediments of Minnesota’s rivers, creeks and lakes
  • Personal care product active ingredients triclosan (TCS) and triclocarban (TCC) detected in all samples takenupstreamanddownstreamof wastewater treatment plants
  • Among the two known endocrine disruptors monitored, triclocarban was more abundant than triclosan
  • Study adds tobody of scientific work calling into question the widespread use of antimicrobial compounds that offer nomeasurable benefit for the average consumer

In our zest for cleanliness, have we permanently muddied our nation’s waters?     A science team from Arizona State University, in collaboration with federal partners, has completed the first statewide analysis of freshwater bodies in Minnesota, finding widespread evidence of the presence of active ingredients of personal care products in Minnesota lakes, streams and rivers.   These products are a billion dollar industry and can be found in antimicrobial soaps, disinfectants, and sanitizers to scrub our hands and clean countertops. Hundreds of antimicrobial products are sold in the U.S., many marketed with efficacy claims that remain elusive due to the short duration of the average consumer’s handwashing practices. The fate of these products can be traced from home use to sewers to wastewater treatment plants to eventually, downstream bodies of water.    The research team focused on two active ingredients found prominently in anti-bacterial soaps −triclosan and triclocarban− which have come under scrutiny by the EPA and FDA due to their environmental and human health concerns. These compounds persist for decades in the environment, and both triclocarban and triclosan are among the top ten pharmaceuticals and personal care products most frequently found in the environment and in U.S. drinking water resources.

“This study underscores the extent to which additives of antimicrobial consumer products are polluting freshwater environments in the U.S.; it also shows natural degradation processes to be too slow to counter the continuous environmental release of these endocrine disrupting chemicals,” said Halden, director of Environmental Security at the Biodesign Institute and professor in the Ira A. Fulton School of Sustainable Engineering and the Built Environment. Halden’s research focuses on the interconnectedness of the water cycle and human health, with specialemphasis on the role of manmade products and human lifestyle choices on environmental quality.

In a previous study, Halden’s team found significant concentrations of harmful soap-related chemicals dating back to the 1950’s in sediments of Jamaica Bay and Chesapeake Bay, into which New York City and Baltimore discharge their treated domestic wastewater, respectively.

Upon their use, triclosan and triclocarban are absorbed through the skin and hence contaminate human blood, urine, and even breast milk. Ultimately, these chemicals together with the pharmaceuticals we use end up in our sewage and surface waters. In 2002, the USGS published a landmark study that showed 80 percent of 139 streams sampled from across 30 U.S. states were found to contain measurable levels of organic wastewater contaminants. The human health risks associated with these personal care product chemicals are still not fully understood despite them being used for decades.

In the ASU study, river, creek and lakebed sediment samples from 12 locations upstream and downstream of wastewater treatment plants were analyzed for the presence of antimicrobial compounds.

For Halden’s team, which consisted of postdoctoral researcher Benny Pycke, environmental engineering graduate student and first author Arjun Venkatesan, the results showed that overall concentrations of triclocarban were 3- to 58-times higher than those of the more frequently monitored triclosan.

“We were able to detect these two compounds both upstream and downstream of suspected input sources, and the levels of the antimicrobial soap ingredient triclocarban were usually higher compared to triclosan,” said Venkatesan. “Although triclosan is used in a larger number of formulations and personal care products, we found triclocarban to be more abundant in freshwater environments.” The team also found degradation products of TCC but transformation of this antimicrobial is known to be very slow in natural environments.

“Also, we expected to find these compounds mostly downstream of wastewater treatment plants; but when we consistently found detectable levels upstream and downstream, we realized that there are probably multiple sources contributing to the contamination of these sites, potentially including additional wastewater treatment plants further upstream and runoff from sites where antimicrobial-laden sewage sludge had been applied.”

“Every site is essentially downstream of something,” added Pycke. A site in the immediate vicinity of a wastewater treatment plant near Duluth (St. Louis Bay at Lake Superior) had the greatest concentration of triclocarban and its lower chlorinated derivatives, and the Duluth site and Shagawa Lake site had concentrations three times higher than river and creek sediments. There was a strong correlation between the level of contamination with wastewater treatment plant discharge, stream flow and the population density of the surrounding region.

“As the name suggests, these antimicrobial compounds (triclosan and triclocarban) are incompatible with biological wastewater treatment infrastructure paid for with tax dollars,” said Halden. “Municipalities in Minnesota and across the U.S. work hard using state?of?the?art equipment to keep our freshwater environments clean but they cannot control what consumers, misled by aggressive marketing, discharge into the sewage collection system.”

Wherever antimicrobial personal care products are in use, water and sediment have been contaminated, a situation that certainly is not unique to the state of Minnesota. “Regulatory agencies are aware of the overuse of antimicrobials but no state or federal restrictions have been implemented yet for either triclosan or triclocarban,” said Halden. “Aside from ecological concerns, widespread environmental occurrence of antimicrobials also is a potential public health concern because unwarranted use of antimicrobials can promote drug resistance of human pathogens.”

Halden’s research is developing engineering solutions to clean up environments impacted by antimicrobial compounds. However, he emphasizes that the best solution right now in combating this pollution is for consumers to limit their use of antimicrobial personal care products that, ironically, provide no measurable health benefits to the average consumer, as determined by an expert panel convened by the Food and Drug Administration in 2005.

For this project, ASU was supported by funding from the National Institute of Environmental Health Sciences.

In addition to Halden’s appointment as Director of Environmental Security at ASU’s Biodesign Institute, he holds the title of professor in the School of Sustainable Engineering and the Built Environment, at the Ira. A. Fulton Schools of Engineering, ASU, and adjunct associate professor of Environmental Health Sciences, at the Johns Hopkins Bloomberg School of Public Health.