Major grant awarded for study of tuberculosis

- By Stephanie Pappas

Gary Schoolnik

Researchers at the School of Medicine are working to discover the secrets of one of the world's most prevalent diseases: tuberculosis. A new project, funded by a $19.8 million grant from the National Institute of Allergy and Infectious Diseases, will bring together a global team of experts to learn how the tuberculosis bacterium behaves in human cells.

Tuberculosis infections can lie dormant in the lungs for years. According to the World Health Organization, one-third of the world's population is infected. Five to 10 percent of those people will develop active tuberculosis; about 1.6 million will die. But little is known about how tuberculosis functions in the human body.

Gary Schoolnik, MD, professor of medicine and of microbiology and immunology, who will lead the research team, wants to find out. He's no stranger to collaboration in the name of TB research. He and his colleagues have already established an online tuberculosis genome and gene expression database and are investigating how TB genes behave in infected tissue. The new project will use systems biology to take that research one step further.

Schoolnik, who is also associate director for the Institute for Immunity, Transplantation and Infection and senior fellow in the Woods Institute for the Environment, wants to know what the bacteria do, and when, to stay alive inside host cells. This means looking at the entire biological system of the pathogen: DNA, RNA, proteins, lipids, carbohydrates and metabolic molecules.

'Nothing is particularly chaotic,' he said. 'All of these processes are being controlled by a highly evolved and sophisticated regulatory network.'

To find out how the network functions, Schoolnik and his team will grow TB colonies in macrophages, the immune cells that TB in the lungs calls home. Then they'll track what molecules are produced, when they are produced, and which genes are active during each stage of production.

It's a big project with more diverse data than any one researcher could ever analyze. Instead, the member institutions involved in the effort will take a divide-and-conquer approach. When the separate analyses are done, computational biologists at the Broad Institute of MIT and Harvard will build models to predict TB's behavior in different circumstances.

Schoolnik hopes the models will help develop new treatments for tuberculosis. With 9.2 million new cases of active TB each year, the disease is a global killer on the scale of malaria and HIV, he said. And HIV patients who are infected with TB have a much higher mortality rate than those who don't have tuberculosis. 'When TB and HIV come together in a patient, it is a kind of evil conspiracy,' Schoolnik said.

Collaborative research like his may someday break the conspiracy wide open. 'We were able to assemble this incredible group of people who are world-class experts,' Schoolnik said. 'The sum is far greater than the parts.'

The Max Planck Institute for Infection Biology in Berlin, Brigham and Women's Hospital of Harvard, PDL Labs of Menlo Park and the Seattle Biomedical Research Institute are also collaborating with Stanford on the project.

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu.

2023 ISSUE 3

Exploring ways AI is applied to health care