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.

 

Story Source:

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.

Real-Time Search

Social networking is changing the way we find information.

Mobile 3-D

Smart phones will take 3-D mainstream.

Engineered Stem Cells

Mimicking human disease in a dish.

Solar Fuel

Designing the perfect renewable fuel.

Light-Trapping Photovoltaics

Nanoparticles boost solar power’s prospects.

Social TV

Relying on relationships to rebuild TV audiences.

Green Concrete

Storing carbon dioxide in cement.

Implantable Electronics­

Dissolvable devices make better medical implants.

Dual-Action Antibodies

Fighting cancer more efficiently.

Cloud Programming

A new language will improve

The-Scientist.com, April 2010, by Edyta Zielinska  –  The question of how T cells escape the thymus and enter the circulation to fight infections has finally been answered.

“These findings will be taught in textbooks down the road,” Kristin Hogquist from the University of Minnesota, who was not involved in the research, wrote in an email. “This is a fascinating study,” she added.

Scientists have long wondered how T cells exit the thymus, where they mature. The thymus is threaded with both blood vessels and lymphatic vessels (containing lymphocytes suspended in a clear fluid), so researchers didn’t know which exit route T cells took.

New findings published this week in Science have settled the debate: Mature T cells escape the thymus via blood cells rather than lymphatic vessels.

Marcus Zachariah and Jason Cyster from the University of California in San Francisco investigated the question by looking at the receptor S1P1, expressed by mature T cells just before they exit the thymus. The receptor drives cells to areas, such as the blood, that are rich in S1P — the receptor’s ligand. However, it was recently shown that the S1P ligand in the blood wasn’t sufficient to draw T cells out of the thymus, Yousuke Takahama, from the University of Tokushima, who wasn’t involved in the research, said in an email.

The researchers observed T cells expressing the S1P1 receptor, and noticed that these cells accumulated at blood vessels of the thymus — specifically, near pericytes, a cell type that creates a sheath around blood vessels. This suggested that the S1P ligand on these pericytes was attracting the cells to that location.

When researchers deleted the S1P expression on pericytes only, T cells were unable to exit the thymus. “This study shows that S1P-mediated thymocyte egress is not a single-step process regulated by blood-borne S1P, but a multiple-step process,” regulated by both the S1P on the pericytes and in the blood, said Takahama.

M.A. Zacharia, J.G. Cyster, “Neural Crest-Derived Pericytes Promote Egress of Mature Thymocytes at the Corticomedullary Junction,” Science, published online April 22, 2010, doi:10.1126/science.1188222.

For Immediate Release:  April 26, 2010
Media Inquiries:  Dick Thompson, 301-796-7566; dick.thompson@fda.hhs.gov
Consumer Inquiries:  888-INFO-FDA

FDA Changes Process for Medical Device Advisory Committees
Goal is improved discussion and flow of information

The U.S. Food and Drug Administration today announced that it will change the way its expert panels review and discuss data and information during public hearings on medical devices under review for premarket approval, effective May 1, 2010.

The changes were prompted by an increasing number of medical device advisory panel meetings in recent years. In 2008, there were 10 panel meetings covering 14 major topics. In 2009, there were 17 meetings on 20 topics, and 2010 is on track to surpass those numbers, according to the FDA’s Center for Devices and Radiological Health (CDRH).

The increased activity has created challenges for CDRH and the way it operates panel meetings. In accord with current agency policy and guidance for advisory committees, the changes address staffing issues, voting procedures, and other items related to information presentation and flow of discussion.

“These changes are expected to empower the agency to make more effective decisions that are informed by more clear and focused discussion by panel experts,” said CDRH Director Jeffrey Shuren, M.D.

In the past, panel discussions have not always reflected a panel’s final vote on approvability. Now, instead of voting on the approvability of premarket approval applications, including conditions of approval, the panel will vote on the safety and effectiveness of a device and the device’s risk versus its benefit.

“By making this change in voting procedure, panel members will address key scientific issues during their discussions, which will be reflected in their votes,” Shuren said. “The change also will allow panel members to address issues related to their area of expertise instead of regulatory issues that may be unfamiliar to them.”

In addition, panels will vote by ballot instead of by a show of hands. While the votes will be publicly tallied so that panel members can be identified by their vote, the ballot process allows each panel member to cast his or her vote without immediate influence by other votes.

There are many issues involved in the FDA’s review of a medical device. Historically, the FDA’s presentations to panels included comments on approvability. With the changes, the FDA’s presentations will continue to include reviews of the agency’s data analysis, but will no longer include comments on approvability.

Before the changes, the agency medical device reviewers presented a unified, consensus analysis of supporting data. Now, reviewers will present together with data and analysis, the range of scientific opinion in the group. This move will allow more in-depth discussion on safety and effectiveness and risk versus benefit of the device under consideration..

The FDA and CDRH will continue to evaluate panel procedures and make changes when necessary. A detailed description of changes to panel operations can be found here1.

For more information:

Your Target Health Inc. Blogger is at the Experimental Biology Meeting in Anaheim, CA

 

WebMD.com, by Kathleen Doheny, April 27, 2010 (Anaheim, California) — Eat more like a Greek, and less like a typical American, and you may be doing your brain a favor, new research suggests.

Older adults who adhere to the heart-healthy Mediterranean diet — rich in fruits, vegetables, olive oil, legumes, fish, and moderate amounts of wine — appear to have less mental decline with age, according to one of the latest studies on the health benefits of eating like a Greek.

”Those who adhered most closely to the Mediterranean diet performed as if they were two years  younger,” says study researcher Christy Tangney, PhD, a researcher at Rush University Medical Center, Chicago, who presented her findings Monday at EB 2010, the annual Experimental Biology meeting.

Exactly why the diet, already known for its heart-healthy effects, may protect brain function isn’t known, Tangney tells WebMD, but her research builds on other studies finding the diet preserves thinking and intellectual skills.

”I think there’s a strong cardiovascular component,” she says. Some of the diet components, such as the phytochemicals from fruits and vegetables, are thought to protect against neuron loss, she says.

Following the Mediterranean Diet

Tangney and her colleagues followed 3,790 men and women enrolled in the ongoing Chicago Health and Aging Project. The average age of the participants was 75, but all were over age 65. The follow-up averaged more than seven years.

The men and women answered a food-frequency questionnaire, spelling out in detail which components of the diet they ate and how often. The highest possible score for adherence to the Mediterranean diet is 55, but as Tangney notes, “No one followed it perfectly.”

Tangney then classified their adherence to the diet as low, medium, or high. Low followers scored 12 to 25, medium 26 to 29, and high 30 to 45.

The researchers administered several tests of mental function, such as short- and long-term recall, and compiled those scores as a ”global cognitive score.” The tests were given every three years.

Those in the top group knocked two years off their test scores, she says. For instance, if they were 65, they scored in the typical range for a 63-year-old.

There was some effect in the medium group, Tangney says, but no effect in the group that adhered the least.

The beauty of the finding, Tangney tells WebMD, is that following the diet perfectly isn’t necessary to get a brain-protective effect. “When someone incorporates a diet rich in fruits and vegetables and non-refined grains such as cereals and breads and breaks it up with a little wine, there appears to be at least some protection against cognitive aging,” she says.

While Tangney’s team didn’t inquire about exercise habits, she says physical activity would be ideal to add to the Greek-like diet. “The true Mediterranean diet advocates lots of physical activity,” she says.

Second Opinion

The study results ”are significant in that it tells us something may be going on” with the Greek-like diet and mental skills, says Bruce Semon, MD, PhD, a Milwaukee doctor who reviewed the study findings for WebMD.

”It’s a moderate effect,” he says of the two-year improvement found in the study.

Because the researchers looked at the diet as a whole, he says, it’s difficult to separate out which food or foods deserve credit for preserving brainpower.

Tangney says that’s a plus of the study. Many studies have focused on individual nutrients and their effect on health.

But her research looks at the ”big picture” of the Mediterranean diet and finds benefits for those who follow it closely, but not perfectly.

Her advice? ”Eat lots of whole grains, legumes, and beans. Have an occasional glass of wine.”

SOURCES:

Christy Tangney, PhD, researcher, Rush University Medical Center, Chicago.

Bruce Semon, MD, PHD, researcher, Wisconsin Institute of Nutrition, Milwaukee.

EB 2010, Experimental Biology Meeting, Anaheim, Calif., April 24-28, 2010.

Sir Paul Nurse nominated as next President of the Royal Society

Paul Nurse PhD
 

Published Date: 23 April 2010

The Council of the Royal Society has agreed to nominate Nobel Laureate Sir Paul Nurse to be the new President of the Royal Society, it was announced today (23 April 2010).  

Following consultation with Fellows of the Royal Society, the Council of the Royal Society, selected Sir Paul as its nominated candidate to succeed Martin Rees.  Lord Rees completes his five-year term on 30 November 2010, the 350th Anniversary of the founding of the Society.

Fellows will be asked to indicate their support for the Council’s nominated candidate for President on the ballot paper for the annual election of Council members. The result of the ballot will be confirmed at the Council meeting on 8 July 2010.

Paul Nurse is a geneticist who works on what controls the division and shape of cells. He was Professor of Microbiology at the University of Oxford, CEO of the Imperial Cancer Research Fund and Cancer Research UK, and is presently President of Rockefeller University New York. He was awarded the Nobel Prize for Physiology or Medicine in 2001 and the Royal Society Copley Medal in 2005. He will be returning to the UK at the end of the year.

There have been 59 Presidents of the Royal Society since it was founded in 1660. Previous Presidents of the Royal Society have included Christopher Wren, Samuel Pepys, Isaac Newton, Joseph Banks, Humphry Davy, and Ernest Rutherford.