Can Laughing Give You a Workout?
GoogleNews.com, by Madison Park, April 29, 2010, (CNN) — Rolling on the floor laughing, giggling until your stomach hurts, guffawing and slapping your knees — sometimes laughing can feel like a workout.
Studies have shown that mirthful laughter, the kind that stems from real joy, relieves stress, lightens mood and confers health benefits.
Since the concept of laughing for health surfaced in the 1970s, studies have indicated it can decrease cortisol and epinephrine (the hormones that regulate stress), help reduce blood vessel constriction and boost immune function.
One small new study takes that notion further by suggesting laughter could be as beneficial as exercise. But it’s facing some skepticism.
The new research suggests repetitive laughter can affect hormones in the same way that exercise does. Dr. Lee Berk, a preventive care specialist and researcher at Loma Linda University, presented his findings this week at the 2010 Experimental Biology conference in Anaheim, California.
In the study, 14 volunteers had their blood pressures and blood samples taken before and after watching two videos — one was the violent 20 minutes of the movie “Saving Private Ryan” and the other was a 20-minute clip from comedies or stand-up routines.
After watching the funny videos, the volunteers had changes in their hormones that regulate appetite. Like the mechanisms seen after exercise, the appetite-repressing hormone leptin decreased. Ghrelin, which makes people hungry, increased.
This doesn’t mean that the volunteers became hungrier; instead, the effect struck “a good balance” between the two hormones, Berk said. After watching the violent video, the subjects showed no statistically significant change.
These initial findings do not mean a person can get healthy by skipping exercise and watching comedy on the couch.
“It’s not rocket science that exercise is good for you,” Berk said. “It adds years to your life.”
Berk’s study has limitations, said Mary Bennett, director of Western Kentucky University School of Nursing, who has published papers on laughter.
When asked whether the effects of laughter are similar to exercise, she said. “That’s too soon to say. I’d want a side-by-side study when they do so many different things.”
Bennett also noted that Berk’s study was “pretty small. Most medical studies you want to see more.”
Berk acknowledged the sample size of 14 is small. Major sources of research dollars such as the National Institutes of Health do not fund projects that examine issues such as laughter, so these studies tend to be smaller, he said.
The topic needs further research, he said.
“The reality is laughter is good for you,” Berk said. “It makes us feel good. The dopamine is there. A merry heart is good medicine. There is plenty of other data to support that.”
Dr. Michael Miller, director of the Center of Preventive Cardiology at the University of Maryland Medical Center, recommends laughter as part of a heart healthy program for patients.
“When you laugh for 15 minutes, the increase in the diameter of the blood vessel is similar to what you get when you run, jog or do aerobic-like activity,” he said.
A 2005 study by Miller found that laughter caused the tissue in the inner lining of blood vessels, known as endothelium, to expand allowing more blood flow.
“It opens the blood vessel up and prevents platelets from clumping. It has a lot of heart-protective characteristics,” he said.
Another study conducted by Miller in 2009 compared responses from 150 people who had suffered heart problems and another 150 who didn’t. The results showed that those who had suffered heart attacks or bypass surgery were less likely to find humor in everyday life and felt more hostility.
Although the physiology of laughter is not well-understood, it has plenty of devotees, some of whom have started laughercise and laughter yoga classes. In these sessions, participants force themselves to laugh for health reasons.
Even when the laughter is contrived, “you will get the benefit every time you do it,” Berk said. “You don’t have to hear a joke to get the benefit.”
Marilyn Galfin, who describes herself as a certified laughter leader and a professional clown, plans to start laughter classes in New York City for women who are trying to become active.
“When you’re laughing, everything is moving,” she said. “The internal organs are moving. You’re getting things moving and starting to burn calories.”
Galfin envisions participants in the class laughing, moving and playing children’s games such as tag.
Children might not be such a bad example, said Miller.
“Kids laugh as much as 300 times a day; we do about 10 times less,” he said. “True, kids laugh at everything. They don’t deal with day-to-day stress, they’re much more lighthearted. They don’t take themselves too seriously.”
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Implanted under the skin, an array of light-emitting diodes could signal the concentration in the blood of biomarkers such as insulin. Over time, the array will dissolve away, eliminating the need for surgery to remove the implant. Flexible silicon electronics (inset) are held in place with a silk film. Incorporating antibodies or enzymes into the film will allow devices to detect biomarkers. Credit: Bryan Christie Design
Dissolvable devices make better medical implants
MIT Technology Review, May/June 2010, by Katherine Bourzac – The next generation of implantable medical devices will rely on a high-tech material forged not in the foundry but in the belly of a worm. Tufts University biomedical engineer Fiorenzo Omenetto is using silk as the basis for implantable optical and electronic devices that will act like a combination vital-sign monitor, blood test, imaging center, and pharmacy–and will safely break down when no longer needed.
Implanted electronics could provide a clearer picture of what’s going on inside the body to help monitor chronic diseases or progress after surgery, but biocompatibility issues restrict their use. Many materials commonly used in electronics cause immune reactions when implanted. And in most cases today’s implantable devices must be surgically replaced or removed at some point, so it’s only worth using an implant for critical devices such as pacemakers. Silk, however, is biodegradable and soft; it carries light like optical glass; and while it can’t be made into a transistor or an electrical wire, it can serve as a mechanical support for arrays of electrically active devices, allowing them to sit right on top of biological tissues without causing irritation. Depending on how it’s processed, silk can be made to break down inside the body almost instantly or to persist for years. And it can be used to store delicate molecules like enzymes for a long time.
Omenetto began working with silk three years ago, when David Kaplan, a biomedical engineer across the hall, asked for help making the material into complex scaffolds for growing new tissues. He boils silkworm cocoons and purifies the resulting solution to create his master ingredient, a water-based solution of the silk protein called fibroin. This solution can be poured into molds to make structures whose features are as small as 10 nanometers across. Omenetto has molded it into a wide variety of optical devices, such as lenses, mirrors, prisms, and optical fibers, all of which could be used to direct light to and from biosensors implanted in the body. Mixing antibodies or enzymes into the silk solution before molding it results in devices that could someday be used to sense low concentrations of just about any biological molecule, from glucose to tumor markers.
Collaborating with Kaplan and materials scientist John Rogers at the University of Illinois at Urbana-Champaign, Omenetto has produced implants that combine silk with flexible silicon electronics. For instance, the group has used silk films to hold in place arrays of tiny silicon transistors and LEDs–a possible basis for implantable devices that will help identify the concentration of disease markers. The researchers have shown that the devices function fine in small animals, with no evidence of scarring or immune response. The silk dissolves, leaving behind a small amount of silicon and other materials used in the circuits.
Another device uses silk as a substrate for a metal electrode mesh designed to replace spike-like electrodes used on the surface of the brain to diagnose and treat conditions such as epilepsy. When doused with saline solution, the silk wraps the mesh around the surface of the brain (even tucking it into the creases), helping the electrodes measure neural activity more precisely. The silk-based electrodes will probably be the first of the group’s devices to be tested in people, perhaps in two to three years.
Omenetto sees other possibilities further in the future: for example, a silk optical fiber could transmit light from an LED array to an implanted silk sensor, which would change color to indicate that a cancer has come back. The device might then release a precisely calibrated dose of a drug. A second silk fiber could transmit that information to the surface of the patient’s skin, where the output might be read by a cell phone. All the components for making such things exist, Omenetto says. Once the pieces are brought together, a little silk will help save lives.
HUNTER: Edward M. Marcotte and colleagues at the University of Texas at Austin have found hundreds of genes involved in human disorders.
The New York Times, April 26, 2010, by Carl Zimmer – Edward M. Marcotte is looking for drugs that can kill tumors by stopping blood vessel growth, and he and his colleagues at the University of Texas at Austin recently found some good targets — five human genes that are essential for that growth. Now they’re hunting for drugs that can stop those genes from working. Strangely, though, Dr. Marcotte did not discover the new genes in the human genome, nor in lab mice or even fruit flies. He and his colleagues found the genes in yeast.
“On the face of it, it’s just crazy,” Dr. Marcotte said. After all, these single-cell fungi don’t make blood vessels. They don’t even make blood. In yeast, it turns out, these five genes work together on a completely unrelated task: fixing cell walls.
Crazier still, Dr. Marcotte and his colleagues have discovered hundreds of other genes involved in human disorders by looking at distantly related species. They have found genes associated with deafness in plants, for example, and genes associated with breast cancer in nematode worms. The researchers reported their results recently in The Proceedings of the National Academy of Sciences.
The scientists took advantage of a peculiar feature of our evolutionary history. In our distant, amoeba-like ancestors, clusters of genes were already forming to work together on building cell walls and on other very basic tasks essential to life. Many of those genes still work together in those same clusters, over a billion years later, but on different tasks in different organisms.
Studies like this offer a new twist on Charles Darwin’s original ideas about evolution. Anatomists in the mid-1800s were fascinated by the underlying similarities of traits in different species — the fact that a bat’s wing, for example, has all the same parts as a human hand. Darwin argued that this kind of similarity — known as homology — was just a matter of genealogy. Bats and humans share a common ancestor, and thus they inherited limbs with five digits.
EMBRYONIC In their quest for drugs that can kill tumors by stopping blood vessel growth, scientists use glass needles to fertilize frog embryos with genes from yeast that also make proteins found in developing human blood vessels.
Some 150 years of research have amply confirmed Darwin’s insight. Paleontologists, for example, have brought ambiguous homologies into sharp focus with the discovery of transitional fossils. A case in point is the connection between the blowholes of whales and dolphins and the nostrils of humans. Fossils show how the nostrils of ancestral whales moved from the tip of the snout to the top of the head.
In the 1950s, the study of homology entered a new phase. Scientists began to discover similarities in the structure of proteins. Different species have different forms of hemoglobin, for example. Each form is adapted to a particular way of life, but all descended from one ancestral molecule.
When scientists started sequencing DNA, they were able to find homologies between genes as well. From generation to generation, genes sometimes get accidentally copied. Each copy goes on to pick up unique mutations. But their sequence remains similar enough to reveal their shared ancestry.
A trait like an arm is encoded in many genes, which cooperate with one another to build it. Some genes produce proteins that physically join together to do a job. In other cases, a protein encoded by one gene is required to switch on other genes.
It turns out that clusters of these genes — sometimes called modules — tend to keep working together over the course of millions of years. But they get rewired along the way. They respond to new signals, and act to help build new traits.
In an influential 1997 paper, Sean B. Carroll of the University of Wisconsin, Neil Shubin of the University of Chicago and Cliff Tabin of Harvard Medical School coined a term for these borrowed modules: “deep homology.”
Since then, scientists have gotten a far more detailed look at many examples of deep homology. Dr. Carroll and his colleagues, for example, recently figured out how the spots on a fly’s wing evolved through rewiring modules. A tiny fly called Drosophila guttifera sports a distinctive pattern of 16 polka dots on its wings. Dr. Carroll and his colleagues discovered that the module of genes that sets the location of the spots is the same module that lays out the veins and sensory organs in the wings of many fly species. The module was later borrowed in Drosophila guttifera to lay down dots, too.
Our own eyes are also the product of deep homology. The light-sensing organs of jellyfish seem very different from our eyes, for example, but both use the same module of genes to build light-catching molecules.
Scientists are also discovering that our nervous system shares an even deeper homology with single-celled organisms. Neurons communicate with each other by forming connections called synapses. The neurons use a network of genes to build a complete scaffolding to support the synapse. In February, Alexandre Alié and Michael Manuel of the National Center for Scientific Research in France reported finding 13 of these scaffold-building genes in single-celled relatives of animals known as choanoflagellates.
No one is sure what choanoflagellates use these neuron-building genes for. The one thing that is certain is that they don’t build neurons with them.
Until now, scientists have simply stumbled across examples of deep homology. Dr. Marcotte wondered if it was possible to speed up the pace of discovery.
The evidence for deep homologies, he reasoned, might already be waiting to be found in the scientific literature — specifically, in the hundreds of thousands of studies scientists have conducted on how various genes worked in various species.
Scientists have identified thousands of genes that can give rise to diseases in humans when they mutate. Other researchers have systematically mutated each of the 6,600 genes in yeast and observed how the mutant yeast fare under different conditions. If Dr. Marcotte could analyze data like these, he reasoned, he might find gene modules doing different things in distantly related species.
Dr. Marcotte and his colleagues amassed a database of 1,923 associations between genes and diseases in humans. They added more than 100,000 additional associations between genes and traits in species including mice, yeast and nematode worms.
The scientists then searched for related genes that produced different traits in different species. They discovered, for example, that five genes known to help build blood vessels were closely related to five genes that yeast cells use to fix their cell walls.
Discovering these shared genes then allowed Dr. Marcotte and his colleagues to make new discoveries. Their database had a total of 67 genes that fix cell walls in yeast. If yeast and humans inherited an ancient gene module, we might use related versions of other yeast genes to build blood vessels.
The scientists studied the 62 other wall-fixing yeast genes. To do so, they found related versions in frogs and watched how each one behaved in the developing frog embryo. The scientists discovered that five of the additional yeast genes also made proteins found in developing blood vessels. To see how important these proteins were for building blood vessels, the scientists shut down, one by one, the genes that carried the instructions for each protein, and observed how frog embryos developed.
“We ended up with a dramatic loss of blood vessels,” said John Wallingford, a University of Texas developmental biologist and co-author of the study. Dr. Marcotte wondered if humans might also share modules with much more distantly related organisms: plants. He and his colleagues expanded their database with 22,921 associations between genes and traits scientists have found in the mustard plant Arabidopsis thaliana.
To their surprise, the scientists discovered 48 modules shared by plants and people. “There was a lot of screaming in the halls for that one,” Dr. Marcotte said.
The scientists picked out one particularly strange module shared by plants and people for closer study. In humans, the genes have been linked to a rare genetic disorder called Waardenburg syndrome. It is caused by a disturbance in a group of cells in embryos called neural crest cells. Normally, the neural crest cells crawl through the embryo and form a strip running along the back. They then give rise to nerve cells, pigment-producing cells and some bones of the skull. People with Waardenburg syndrome have symptoms scattered across the parts of the body produced by neural crest cells. They may include deafness; widely spaced eyes; a white forelock of hair; and white patches on their face.
The scientists discovered that two Waardenburg-linked genes matched mustard plant genes for sensing gravity. If these genes are disabled by a mutation, a plant can’t grow upright.
Dr. Marcotte and his colleagues found three more gravity-sensing plant genes in their database. They decided to see if any of the three also played a role in Waardenburg syndrome.
The scientists found that one of the gravity-sensing plant genes became active in the neural crest cells of frog embryos. When they silenced the gene in those neural crest cells, the embryos became deformed.
Dr. Carroll (who also writes a science column for The New York Times) saw the new research as a logical progression from early studies. “It warms our hearts that deep homology is gaining traction like this,” he said.
“This is a very effective way to find human disease genes,” said David Platchetzski of the University of California, Davis, who was not involved in the study. “You can move forward much more quickly.”
Target Health Inc. attended the Experimental Biology Conference, this week in Anaheim, CA
ScienceDaily.com, April 28, 2010 — Imagine your delight while enjoying your favorite Mexican food — perhaps a fully loaded bean burrito topped with an ample supply of thinly sliced jalepeño peppers. What happens when you bite into a few more peppers than you bargained for? Does this thought conjure up the thought of a little heat? Perhaps even a bit of sweat on the brow?
Indeed, food scientists can tell you that hot peppers contain a substance called capsaicin that not only adds spice to our foods but can actually cause your body to heat up. They hypothesize that plants evolved to contain capsaicin because it protected them from being eaten by insects and other pesky predators. On the contrary, cuisines worldwide rely on capsaicin-packing peppers to add pungency and zing to many traditional foods, and “pepperheads” often choose their meal to purposefully turn up the heat.
But scientists are learning there is more than meets the eye (or should we say taste buds) when it comes to peppers. In fact, there is growing evidence that the body-heat-generating power of peppers might even lend a hand in our quest to lose those extra inches accumulating around our collective national waistline. And fortunately for those of us who don’t appreciate the “burn” of hot peppers, there are plants that make a non-burning version of capsaicin called dihydrocapsiate (DCT) that could have the benefits of peppers without the pungency.
In a study designed to test the weight-loss potential of this DCT containing, non-spicy cousin of hot peppers, researchers at the UCLA Center for Human Nutrition set out to document its ability to increase heat production in human subjects consuming a weight-loss diet. Under the direction of David Heber (Professor of Medicine and Public Health), they recruited 34 men and women who were willing to consume a very low-calorie liquid meal replacement product for 28 days. The researchers then randomized the subjects to take either placebo pills or supplements containing the non-burning DCT pepper analog. Two dosage levels of DCT were tested. At the beginning and end of the study, body weight and body fat were assessed, and the researchers determined energy expenditure (heat production) in each subject after he or she consumed one serving of the test meal.
On April 27, Heber and his research team presented their results at the Experimental Biology 2010 meeting in Anaheim, CA. This presentation is part of the scientific program of the American Society for Nutrition, home to the world’s leading nutrition researchers.
Their data provided convincing evidence that, at least for several hours after the test meal was consumed, energy expenditure was significantly increased in the group consuming the highest amount of DCT. In fact, it was almost double that of the placebo group. This suggests that eating this pepper-derived substance that doesn’t burn can have the same potential benefit as hot peppers at least in part by increasing food-induced heat production. They were also able to show that DCT significantly increased fat oxidation, pushing the body to use more fat as fuel. This may help people lose weight when they consume a low-calorie diet by increasing metabolism.
Note, however, that a limitation to this study was that the researchers only tested the effect of DCT on the thermic response to a single meal. Heber and colleagues also point out that that there might be a different effect in lean vs. obese subjects. But to their credit, this was the first study ever conducted to examine the potential health benefits of DCT consumed together with a very low calorie diet. The bottom line: don’t be afraid to pile on the peppers.
Dr. David Heber, Dr. Amy Lee, Alona Zerlin, Gail Thames, and Dr. Zhaoping Li are all researchers at UCLA’s Center for Human Nutrition in Los Angeles, CA and were coauthors on this paper.
Adapted from materials provided by Federation of American Societies for Experimental Biology
Harvard University, April 29, 2010 — The use of antibiotics to treat bacterial infections causes a continual and vicious cycle in which antibiotic treatment leads to the emergence and spread of resistant strains, forcing the use of additional drugs leading to further multi-drug resistance.
But what if it doesn’t have to be that way?
In a presentation at the American Society for Biochemistry and Molecular Biology’s annual meeting, titled “Driving backwards the evolution of antibiotic resistance,” Harvard researcher Roy Kishony discussed his recent work showing that some drug combinations can stop or even reverse the normal trend, favoring bacteria that do not develop resistance.
“Normally, when clinicians administer a multi-drug regimen, they do so because the drugs act synergistically and speed up bacterial killing,” Kishony explains. However, Kishony’s laboratory has focused on the opposite phenomenon: antibiotic interactions that have a suppressive effect, namely when the combined inhibitory effect of using the two drugs together is weaker than that of one of the drugs alone.
Kishony and his team identified the suppressive interaction in E. coli, discovering that a combination of tetracycline — which prevents bacteria from making proteins — and ciprofloxacin — which prevents them from copying their DNA — was not as good as slowing down bacterial growth as one of the antibiotics (ciprofloxacin) by itself.
Kishony notes that this suppressive interaction can halt bacterial evolution, because any bacteria that develop a resistance to tetracycline will lose its suppressive effect against ciprofloxacin and die off; therefore, in a population the bacteria that remain non-resistant become the dominant strain.
While such a weakened antibiotic combination is not great from a clinical standpoint, the Kishony lab is using this discovery to set up a drug screening system that could identify novel drug combinations that could hinder the development of resistance but still act highly effectively. “Typical drug searches look for absolute killing effects, and choose the strongest candidates,” he says. “Our approach is going to ask how these drugs affect the competition between resistant versus sensitive bacterial strains.”
To develop such a screen, Kishony and his group first had to figure how this unusual interaction works.
“Fast growing bacteria like E. coli are optimized to balance their protein and DNA activity to grow and divide as quickly as the surrounding environment allows,” Kishony explains. “However, when we exposed E. coli to the ciprofloxacin, we found that their optimization disappeared.”
“We expected that since the bacteria would have more difficulty copying DNA, they would slow down their protein synthesis, too,” Kishony continues. “But they didn’t; they kept churning out proteins, which only added to their stress.” However, once they added the tetracycline and protein synthesis was also reduced in the E. coli, they actually grew better than before. They then confirmed the idea that production of ribosomes — the cell components that make proteins — is too high under DNA stress by engineering E. coli strains that have fewer ribosomes than regular bacteria. While these mutants grew a more slowly in normal conditions, they grew faster under ciprofloxacin inhibition of DNA synthesis.
Kishony notes that their preliminary work on the development of a screen for drugs that put resistance in a disadvantage looks promising, and hopes that it would lead to the identification of novel drugs that select against resistance.
Adapted from materials provided by Federation of American Societies for Experimental Biology
Image: Wikimedia commons, V. Brinkmann, Max Planck Institute for Infection Biology
The-Scientist.com, April 2010, by Jef Akst – Salmonella can wreak havoc in (or kill) people infected with HIV — and not for the reason scientists have long assumed.
Instead, a new study in Science shows that Salmonella‘s ability to cause disease in HIV patients does not appear to stem from a weakened or ineffective immune system, but an overactive one that actively protects the bacteria. The findings may help direct research on developing effective vaccines against the pathogen.
“In an HIV-infected person, you would expect that if you’re not seeing clearance of a pathogen, it’s because [the person is] not making any antibodies against that specific pathogen,” said immunologist Susan Moir of the National Institute of Allergy and Infectious Diseases’s Laboratory of Immunoregulation. “But they found the opposite — they found a lot of antibody, but it was directed against the wrong thing.”
Nontyphoidal Salmonella (NTS) are bacteria that infect humans who eat improperly prepared food products, which cause stomach problems in healthy people, but can be fatal in those with HIV — particularly patients living in Africa with limited access to antiretroviral therapy.
To understand the mechanism of infection, immunologist Calman MacLennan and his colleagues at the University of Birmingham in the UK and the University of Malawi in Africa exposed blood samples from healthy and HIV-infected African adults to invasive Salmonella strains. While the blood from healthy individuals successfully killed the invading bacteria, HIV-infected blood was much less effective.
Suspecting that the HIV blood lacked the NTS-specific antibodies needed to kill the pathogen, the researchers measured the levels of immunoglobulin G (IgG) that specifically bind to the bacteria. Surprisingly, the team found that blood samples unable to eliminate the infection had higher levels of IgG than blood samples that could kill Salmonella.
“That’s the paradox,” MacLennan said — blood from HIV patients was less effective at killing the Salmonella, but “these patients have lots of antibodies.”
Mixing blood from healthy and HIV-infected individuals also impaired Salmonella-killing ability, indicating that there was some sort of inhibitory molecule present in the blood of HIV patients. “Instead of [an immune] deficiency, there was something that was inhibiting the normal killing action of the blood,” MacLennan said.
Curiosity peaked, the team did a series of analyses to isolate the inhibitory factor — what turned out to be an antibody specific to lipopolysaccharide (LPS), a membrane protein common to most gram negative bacteria, including Salmonella. But when these antibodies successfully bound to Salmonella, they did not kill it. Furthermore, they prevented the effective antibodies — those targeted towards Salmonella outer membrane proteins — from reaching their targets and clearing the infection.
“Some antibodies were protective, and others were on the contrary facilitating infection,” said immunologist Jean-Laurent Casanova of The Rockefeller University. It’s a “rather unusual finding,” Moir added.
Whether or not this mechanism may be the cause of other opportunistic infections in HIV-infected individuals — particularly other gram negative bacteria with the same LPS molecule on their surface — is up for debate, Moir said. “We don’t know whether this is a very unique situation where all the stars align,” she said, or if it could be more generally applicable in terms of immunity against other infections. MacLennan and his colleagues are currently investigating this question.
Both healthy and HIV-infected individuals had both inhibitory and protective antibodies. The difference seemed to stem from the ratios of the two, with HIV patients having much higher levels of the inhibitory kind relative to the protective ones. Why this is the case, however, is a bit unclear.
One possibility is that, in HIV-infected individuals, gut bacteria leak into the plasma, increasing the amount of circulating LPS, which is common to many different bacteria, and causing the body to generate more antibodies specific to that bacterial protein. “The immune response in HIV [patients] does seem to alter the permeability of the gut wall and the ease with which bacteria can come across the gut and get into the blood,” MacLennan said.
The results may have important implications for the development of a vaccine against Salmonella, Moir said. “If a vaccine can be developed, this study helps in directing the research towards an antibody that’s directed towards the outer membrane proteins, not LPS,” she said. “Stay away from LPS [or] you’ll be making inhibitory proteins.”
Furthermore, “it may have general implications beyond Salmonellosis and HIV as well,” Casanova added. “Beyond HIV-infected individuals, it suggests that if you alter the antibody response, that may precipitate Salmonellosis and perhaps other infectious diseases.”
C.A. MacLennan, et al., “Dysregulated Humoral Immunity to Nontyphoidal Salmonella in HIV-Infected African Adults,” Science, 328:508-12, 2010.
Cells of Salmonella isolated from macrophages. (Credit: Environmental Molecular Sciences Laboratory
University of Birmingham, Great Britain — A study published in the journal Science offers a long-awaited explanation for the link between HIV infection and susceptibility to life-threatening nontyphoidal strains of Salmonella. The research, funded by the Wellcome Trust and GlaxoSmithKline, goes on to identify targets that could be pursued for vaccine development.
Nontyphoidal strains of Salmonella (NTS) usually cause vomiting and diarrhoea in high-income countries and are mainly contracted by consuming infected foods, such as uncooked meat and eggs. NTS can also cause fatal bloodstream infections in people with compromised immunity, such as HIV-infected individuals, and children under two years of age or with malaria, anaemia or malnutrition.
This is a particular problem in Africa where Salmonellae are the most common bacteria to infect the blood. Such bloodstream infections can be treated with antibiotics, but drug resistance is on the increase and there is currently no vaccine available.
“The association between HIV infection and fatal cases of nontyphoidal Salmonella disease has been known since the onset of the AIDS pandemic 26 years ago, but this is the first time we’ve been able to offer a scientific explanation why,” said Dr Cal MacLennan from the University of Birmingham, who led the research.
In an earlier study of African children, the team of researchers working at the Malawi-Liverpool-Wellcome Trust Clinical Research Programme, at the University of Birmingham and the University of Malawi’s College of Medicine, had shown that protective Salmonella-specific antibodies generated in the first two years of life are critical for controlling the infection.
In the new study, the researchers turned their attention to immunity in African adults. While blood samples from HIV-uninfected adults killed Salmonella without difficulty, those from many HIV-infected Africans could not kill Salmonella. Since HIV causes significant defects in the immune system, the team examined whether a lack of these antibodies might account for the absence of killing and explain why HIV-infected adults are particularly susceptible to Salmonella infections.
Contrary to expectations, the team found that blood from HIV-infected adults harboured high levels of antibodies to Salmonella, molecules that normally help the immune system to fight infections. However, unlike the antibodies in healthy adults, these antibodies were unable to kill Salmonella. In fact, antibodies from these people actually stopped the antibodies from healthy adults from killing Salmonella.
The team went on to show that this difference in ability to kill Salmonella is due to the part of the Salmonella that the antibodies bind to. The protective ‘killing’ antibodies bind to structures on the surface of the bacteria known as outer membrane proteins. This then allows the immune system to destroy the Salmonella bacteria.
On the other hand, large numbers of antibodies in HIV-infected Africans bind to a structure that sticks out from the surface of the Salmonella known as LPS (lipopolysaccharide). These ‘blocking’ antibodies appear to divert the immune system away from the surface of the bacteria and stop the killing antibodies from doing their job.
When the researchers specifically removed the blocking antibodies from HIV-infected blood samples, they found killing antibodies present in the blood that could once again kill the bacteria. This shows that people infected with HIV still have the protective killing antibodies generated in the first two years of life that can control Salmonella infection, but the excess of blocking antibodies stops the killing antibodies from working.
“We normally think of HIV patients as being more susceptible to bacterial infections because of deficiencies in their immune systems, and often they have problems making antibodies when given vaccinations. In the present study, we found that it’s actually an excess of antibodies that causes the problem,” explained Dr MacLennan.
“The findings are important because LPS is currently being investigated as a potential target for a vaccine. Our observations that antibodies targeting LPS can actually impede the protective immune response to Salmonella would caution against this, suggesting that such a vaccine could do more harm than good.”
A vaccine that protects both young children and HIV-infected adults from fatal cases of NTS is urgently needed in Africa. The findings from this study suggest that the outer membrane proteins could potentially serve as alternative vaccine targets and this is an area that the team is currently investigating.
Adapted from materials provided by Wellcome Trust.
Two for the price of one: Antibody drugs work by binding to antigens such as extracellular proteins or receptors on a cell’s surface, blocking their ability to function or targeting them for destruction by the immune system. Genentech’s new antibodies can bind to two different antigens, potentially reducing the number of drugs required to treat diseases. The antibody colored yellow can bind only to a receptor on the surface of a cancer cell. The green-colored antibody can bind only to an extracellular protein that promotes tumor growth. The new antibody (red) can bind to both the surface receptor and the extracellular protein. Credit: Bryan Christie Design
Fighting cancer more efficiently
This article is part of an annual list of what we believe are the 10 most important emerging technologies. See the full list below.
MIT Technology Review, May/June 2010, by Sabin Russell – At Genentech’s sprawling headquarters south of San Francisco, senior scientist Germaine Fuh has been genetically redesigning two of the company’s most lucrative cancer drugs. One, Herceptin, is a monoclonal antibody that shuts down HER2, a growth accelerator in about 20 percent of breast tumors. The other, Avastin, is an antibody that blocks a protein that stimulates the formation of tumor-feeding blood vessels. Last year the drugs had combined sales of $11 billion; a full course of Herceptin at wholesale costs about $43,000, while treating a breast cancer patient with a full course of Avastin costs about $55,000. Fuh’s goal: to show she can provide greater benefit for people fighting breast cancer by combining the action of the antibodies in one molecule. Last year, she and her coworkers showed that a modified version of the Herceptin antibody not only shut down the HER2 receptor in mice but also locked onto VEGF, Avastin’s target.
Designing such “dual-specific” antibodies could help solve a major problem with chemotherapy drugs: cancer cells can become resistant to them, mutating in ways that allow them to dodge the medication’s action. Doctors often mix various chemotherapy drugs in an effort to kill cancers before they can exploit this escape mechanism. Having a single drug that can hit the cancer from multiple directions would simplify treatment.
A single monoclonal antibody that could do the work of two is also attractive from a business perspective. It might cost half as much to manufacture as two separate antibodies, and the path to regulatory approval might also be shorter and less expensive, involving one set of clinical trials instead of multiple trials for two separate drugs in various dosage combinations. Genentech has started trials to determine whether Herceptin and Avastin together will fight breast cancer better than either used alone, but the cost of such studies is a big disincentive to doing them regularly.
Fuh’s research into whether one antibody drug could be redesigned to do the work of two began six years ago. An antibody, one of the immune system’s most robust weapons, is a Y-shaped protein about 10 nanometers long. At the tip of each branch is an active site, which grabs a specific molecule on an invading microbe or cancer cell. Swarms of antibodies disable the invader, marking it for destruction by white blood cells or other immune molecules.
Fuh notes that many mammalian antibodies have some ability to bind to a second antigen, but typically they do so weakly. Her goal was to exploit this ability while making both bonds tight and functional. Fuh’s team induced subtle mutations at the tips of Herceptin and screened 10 billion mutant clones for activity against VEGF. They netted several candidates–including one with active sites that could bind to both HER2 and VEGF strongly enough to limit tumor growth.
Genentech, now a wholly owned subsidiary of Swiss pharmaceutical giant Roche, is using this technique to develop another dual-specific drug, which may soon be ready for clinical trials. Fuh won’t disclose the details of what the drug is for and will only say, “Right now, we are very close.”
Meanwhile, her experiments have fueled interest in the overall potential of such drugs. “The two-for-one drug concept is important, especially for indications like cancer,” says Carlos Barbas III, a professor of molecular biology at the Scripps Research Institute in La Jolla, CA. Barbas is the founder of CovX, a company working on a different approach to making dual-specific antibodies (Pfizer acquired it in 2008). Despite the competition, he praises the accomplishment of the Genentech team as “a beautiful piece of antibody engineering.”
The implications of Fuh’s research are indeed far-reaching. If the concept proves successful, antibodies that stick to two targets might be used to treat infectious diseases as well as cancer–offering the promise of drugs that work better and cost less.
Each year, MIT Technology Review selects what it believes are the 10 most important emerging technologies. The winners are chosen based on the editors’ coverage of key fields. The question that we ask is simple: is the technology likely to change the world? Some of these changes are on the largest scale possible: better biofuels, more efficient solar cells, and green concrete all aim at tackling global warming in the years ahead. Other changes will be more local and involve how we use technology: for example, 3-D screens on mobile devices, new applications for cloud computing, and social television. And new ways to implant medical electronics and develop drugs for diseases will affect us on the most intimate level of all, with the promise of making our lives healthier.
Social networking is changing the way we find information.
Smart phones will take 3-D mainstream.
Mimicking human disease in a dish.
Designing the perfect renewable fuel.
Nanoparticles boost solar power’s prospects.
Relying on relationships to rebuild TV audiences.
Storing carbon dioxide in cement.
Dissolvable devices make better medical implants.
Fighting cancer more efficiently.
A new language will improve