Major Breathrough in TB Research: Questions answered!

After three decades of searching, the random screening of a group of compounds against the bacterium that causes pulmonary tuberculosis has led scientists to a eureka discovery that breaks through the fortress that protects the bacterium and allows it to survive and persist against treatments.

The two findings, which occurred at Colorado State University, are published today in Nature Chemical Biology.

The article describes the discovery of an important cell function in the mycobacterium that causes tuberculosis which allows the mycobacterium to survive. The researchers also discovered a compound that prevents this cell function.

The bacterium that causes tuberculosis is extremely difficult to kill and current tuberculosis drugs on the market don’t do well to treat it. Six months of multiple antibiotics are generally required to treat tuberculosis in most people, and many current drugs no longer work because of resistant strains of the bacterium that causes tuberculosis. Scientists hope that finding new drugs to kill the bacteria in ways different than current drugs will help tackle those strains.

Cell envelopes form a virtually impenetrable bubble around the bacterium cell and protect it. Mycolic acids are key portions of this bacterium’s cell envelope. They are made inside the cell, but have to cross the cell membrane, with the help of a transporter, to reach their final location in the cell envelope.

“Without mycolic acids in the cell envelope, the bacteria die,” said Mary Jackson, one of the leading researchers on the project. Jackson is a professor in the Department of Microbiology, Immunology and Pathology.

“While randomly testing a group of compounds against the bacterium in the lab, we found one class of compounds that powerfully stops the growth of the bacterium, a significant finding on its own.

When we looked closer, we found that the compounds stopped a transporter from moving mycolic acids from inside to outside the cell, which also means this discovery identified a new method of killing the bacterium.

Scientists have been trying to find the transporter of mycolic acids for decades, knowing that understanding how to stop mycolic acids from reaching the surface of the cell could lead to new tuberculosis treatments.

“If mycolic acids cannot be transported, the tuberculosis bacterium cannot grow,” said Mike McNeil, co-researcher on the project with Jackson and also a professor in the Department of Microbiology, Immunology and Pathology at CSU.

“It is like a factory making bricks and no way to get them to the construction site. It is a long, hard road to develop new, badly-needed tuberculosis drugs. Still, we are optimistic that this research will strongly contribute to the worldwide crusade to diminish suffering and death caused by tuberculosis.”

Jackson, McNeil and partner researchers from CSU and St. Jude Children’s Hospital in Memphis also note that there are other potential transporters in the bacterium that resemble the one just found.

“We hope that our work also will pave the way to understanding what those transporters do in the cell and finding how to target them to kill the mycobacteria,” Jackson said.

Tuberculosis causes the death of more than 1.5 million people around the globe each year.

Benlysta® - A Breakthrough in Lupus Treatment

Scientific advances at The Scripps Research Institute were key to laying the foundation for the new drug Benlysta® (belimumab), approved today by the U.S. Food and Drug Administration.

Benlysta®, which treats the most common type of lupus, is the first in a new class of pharmaceuticals that prevents the body from attacking its own critical tissues.

“I am deeply gratified that our scientific findings have proven so valuable to drug discovery,” said Richard A. Lerner, MD, president of Scripps Research. “This development underlines the importance of basic academic science in laying important groundwork for life-saving medical advances.”

Benlysta®, developed by GlaxoSmithKline and Human Genome Sciences, is the first new drug treatment for lupus in 50 years.

Short-Circuiting the Cycle of Lupus
Benlysta® was approved for systemic lupus erythematosus, a chronic, life-threatening inflammatory disease affecting the joints, skin, kidneys, blood, heart, and lungs. It is often simply referred to as “lupus” (although there are other types of lupus, including one that affects solely the skin).

Estimates of the number of Americans affected by sytemic lupus erythematosus range from 161,000 to 1.5 million, according to the U.S. Centers for Disease Control. Lupus can occur at any age, but first appears largely in 15- to 40-year-olds, the majority of whom are women.

Lupus is an autoimmune disease, which occurs when a person’s body produces an immune response against its own tissues instead of solely attacking foreign invaders such as viruses, bacteria, and other toxins.

Symptoms can include debilitating fatigue, painful and swollen joints, fever, skin rash, and kidney problems.

The disease can also lead to arthritis, kidney failure, heart and lung inflammation, central nervous system abnormalities, inflammation of the blood vessels, and blood disorders.

Benlysta® (itself a type of immune molecule) acts by targeting a specific protein called B-lymphocyte stimulator, or BLyS, involved in stimulating the “autoantibodies” causing lupus and certain other autoimmune disorders.

Benlysta® is the first approved drug that disables BLyS, thus preventing the immune system’s destructive attacks against the body.

The Foundation
In the 1980s the therapeutic potential of antibodies — which recognize a wide range of foreign pathogens, then alert the immune system to the presence of the invaders — was widely recognized, as they are an important part of the body’s natural system for fighting illness.

But tapping that potential had proven difficult. Researchers at the time were working mainly with short snippets of antibodies and testing their effects through a slow and painstaking petri-dish process.

But Lerner led a Scripps Research team that made two critical advances to transform the field, ultimately leading to the discovery and development of drugs such as Benlysta®.

The researchers first developed a method of combining different pieces of antibodies isolated from human or animal cells into proteins long enough to encompass natural antibodies’ most critical portions — the parts actually binding to and neutralizing infectious agents or otherwise unwanted material.

The scientists dubbed this technique “repertoire cloning,” because it allowed them to build libraries of compounds that encompassed the full repertoire of a natural immune system.

This was a game-changing development.

Eliminating the Petri-Dish Bottleneck
But even with an expansive repertoire, putting it to use was a separate problem. It was a second key Scripps Research discovery that helped eliminate the petri-dish bottleneck.

In 1991, Lerner and his colleagues pioneered a technique for employing phage display to facilitate large “combinatorial antibody libraries” to find human antibodies that could be used therapeutically.

Combinatorial antibody libraries allow human antibodies to be identified directly by searching among billions of antibody variants taken from human blood samples to find those that bind to a particular target — such as BLyS — involved in a particular disease.

In this technique, the scientists hijack the inner workings of phages (viruses that attack bacteria). By inserting genetic sequences encoding active portions of antibodies, the researchers are able to make phages displaying on their surfaces the antibody of interest.

These antibody-displaying phage particles can then be tested en masse for their ability to bind to molecules of interest. Successful binders can then be purified and identified as a target for additional research.

With the British Medical Research Council (MRC) Laboratory of Molecular Biology, Scripps Research licensed the inventions to Cambridge Antibody Technology (now part of AstraZeneca) to facilitate exploitation of the technology for creation of new medicines.

In 1999, Cambridge Antibody Technology partnered with Human Genome Sciences, which entered into a co-development and commercialization agreement with GlaxoSmithKline in 2006.

While much technology has changed over the decades, variations of combinatorial antibody libraries are still a mainstay of drug discovery research. Commercialized throughout the 1990s, the promise of this method is now beginning to be realized — today with Benlysta®, tomorrow, Lerner predicts, with other life-saving drugs.

About The Scripps Research Institute
The Scripps Research Institute is one of the world’s largest independent, non-profit biomedical research organizations.

Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neuroscience, and vaccine development, as well as for its insights into autoimmune, cardiovascular, and infectious disease.

Headquartered in La Jolla, California, the institute also includes a campus in Jupiter, Florida, where scientists focus on drug discovery and technology development in addition to basic biomedical science.

Scripps Research currently employs about 3,000 scientists, staff, postdoctoral fellows, and graduate students on its two campuses. The institute’s graduate program, which awards Ph.D. degrees in biology and chemistry, is ranked among the top ten such programs in the nation.

For more information, see www.scripps.edu

Baby vaccine contaminated with pig virus - health - 12 May 2010 - New Scientist

Baby vaccine contaminated with pig virus

SWINE viruses are back - but this time they don't seem to be making anyone sick.

The US Food and Drug Administration (FDA) has reported that stocks of Merck's Rotateq vaccine against rotavirus are contaminated with the pig viruses PCV1 and PCV2, but the agency has not advised doctors to stop using it as the pig viruses aren't known to cause disease in humans, and rotavirus kills roughly half a million infants worldwide each year. An FDA advisory panel said the vaccine's benefits still outweigh its risks.

The FDA plans to monitor recipients for pig virus-related illness. "There will be quite careful monitoring of the people that have received the vaccine and I think that's entirely appropriate," says virologist Stephen Hughes, who advised the FDA on the issue.

Rotavirus vaccines are mainly given to infants in the developing world, where the virus is most likely to kill. In March, a separate rotavirus vaccine, Rotarix, made by GlaxoSmithKline was found to contain PCV1. In that case, the FDA recommended that doctors avoid using Rotarix while it gathers evidence, but the FDA now says it will issue new recommendations on both affected vaccines soon.

H1N1: UKs BMJ Report Extreme Doubts over Tamiflu results

Research published in the British Medical Journal (BMJ) has confirmed that the antiviral oseltamivir, is only effective in reducing by 1 day, the time people have symptoms. It also confirmed that there was no evidence that oseltamivir prevented the most fatal complications, pneumonia.

It comes after the Government and GPs failed to reach an agreement on the swine flu vaccination programme for under-fives, with health visitors and district nurses now set to be asked by local NHS managers to step in.

The BMJ research has questioned the validity of research from Roche, the pharmaceutical giant that makes Tamiflu.

More than a million courses of antivirals including Tamiflu have been given out to people across Britain since the start of the swine flu pandemic.

A review of 20 existing studies was carried out by a team led by experts from the Cochrane Collaboration, which last reviewed the evidence in 2005. Their updated study found Tamiflu "did not reduce influenza-related lower respiratory tract complications".

The drug was found to induce nausea while evidence of adverse reactions to the drug were "under-reported", they said.

Tamiflu was claimed to be effective in treating people preventatively, i.e. after they had come into contact with somebody who was infected, and shortened the length of symptoms in those with swine flu.

But the study criticised some of the evidence available and said Roche had not been able to "unconditionally" provide the information needed. As a result, the team dropped eight trials that were included in their earlier review because they were unable to independently verify the findings.

This leads to further speculation that the mass innoculation of peoples is commercially based, adding to the profits of the pharmaceutical companies, without there being sound medical evidence to back it up.

The power of the pharma lobbyists is such that this conspiracy to defraud the public has extended into the medical and political hierarchy and large incentives are being offered to executives, politicians and medical authorities that support the exploitation of this pandemic.