February 12, 2007
STANFORD, Calif. - Tuberculosis is one of the oldest and most prevalent diseases known to man, yet some of the workings of this clever bacterium remain largely a biological black box. A partnership led by scientists at the Stanford University School of Medicine hopes to pry open that box through a new initiative in which they will amass the world's largest public database on the genes involved in latent TB - an essential tool to help researchers worldwide develop new treatments for the global scourge.
The work is funded by a $7 million grant from the Bill & Melinda Gates Foundation.
Gary Schoolnik, MD, Stanford professor of medicine and of microbiology and immunology, will lead a team of scientists at Stanford, the Broad Institute at MIT and the Harvard School of Public Health in gathering information on the genes that enable the tuberculosis bacteria to persist in the body, quietly primed for action. One of every three people on the planet has latent TB, in which the bacterium lies silently in wait, often for decades, constantly monitoring the body's immune system for the right moment to burst into full-blown disease.
Armed with a trove of gene expression data on latent disease, scientists could search for new treatments to knock out the bacteria before it becomes active and turns lethal, Schoolnik said.
"Understanding the biology of TB in latency is exciting in that we will be trying to break scientific and technical barriers and doing so as part of an international consortium of scientists," said Schoolnik.
Steven Buchsbaum, senior program officer for the Gates Foundation, said, "This grant is an investment in new ways to share data freely among the global TB community. It aims to help the best scientific minds around the world apply the latest knowledge to TB drug development."
Tuberculosis kills some 2 million people every year, or about one person every 18 seconds, making it a leading infectious cause of death worldwide, according to the World Health Organization, which in 1993 declared it a global emergency. The rise in TB has been fueled in part by the AIDS epidemic, as patients with HIV easily succumb to the disease, the most common opportunistic infection among AIDS patients.
Individuals with latent TB often acquire the bacteria in childhood from coughing adults, but suffer no ill effects until the disease becomes active later in life. Those with latent TB have a 5 to 10 percent risk of having active disease in their lifetimes.
Tuberculosis control efforts worldwide have been hampered by the limitations of current treatments. The drug most commonly used to treat latent TB is isoniazid, which must be taken daily for nine months and has potentially serious side effects, Schoolnik said.
"We could have an enormous impact if we eradicated latent TB. But you can't do that with a drug that requires nine months to be effective, especially since most people with latent TB live in poor countries," he said.
To develop new therapies, scientists need a better understanding of the genes and the metabolic pathways the bacterium uses to maintain itself inside the body, where it typically takes up residence in the lungs.
Scientists already have some knowledge of the basic genetic structure of the bacterium, whose entire genome was sequenced in 1998. And Schoolnik himself has amassed one of the largest collections of TB gene expression data in the world. But there is no central repository available to researchers worldwide for this and other genetic information about the bacterium, he said.
Moreover, some key pieces of information are missing. For instance, while scientists have gene expression data taken from organisms grown in test tubes, there is no available expression data on the TB microbe living in infected human tissues. Tissues of this kind are difficult to obtain, Schoolnik said, because they have to be collected from patients undergoing surgery for other reasons. He and his colleagues at the National Institutes of Health are now collecting tissue samples for analysis from patients with latent tuberculosis in Korea, and hope to expand this effort to include Stanford Hospital as well as other sites in California and in Russia.
Sampling patients is tricky because messenger RNA, from which the key data are extracted, has a half-life of two to three minutes, so physicians must remove the tissue quickly, then plunge it into liquid nitrogen for storage. The RNA extracted from these tissues will later be analyzed using a new ultrasensitive, whole genome expression assay being developed in Schoolnik's lab by senior research scientist Gregory Dolganov, PhD.
"If some of the genes are on, it means they likely have a role in the disease," Schoolnik said. These genes, which could number in the hundreds, and the proteins they produce could serve as possible targets for new drugs.
The project will include some of the same computational scientists who pioneered the development of the Stanford Microarray Database, the largest gene expression database in the world, in partnership with the Broad Institute at MIT. The Broad Institute also maintains a large database of genome sequence data for 25 organisms, including TB.
Schoolnik said he expects that the TB database, which will be available through an easy-to-navigate Web portal, will be used by scientists throughout the world. It is the first time such a comprehensive database has been assembled for a microbe. If it proves successful, it could be used as a model for other disease-causing organisms, he said.
Schoolnik's other Stanford colleagues involved in developing the TB database are Catherine Ball, PhD, director of the Stanford Microarray Database, and Gavin Sherlock, PhD, assistant professor of genetics.
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