CSU TB lab searching for promising drugs

In the early years of the 1900s, people suffering from tuberculosis were drawn to Colorado, seeking relief from the disease. In the last 20 years, tuberculosis has attracted a new breed to the state: researchers intent upon finding a cure.

They come to Colorado State University where, at state-of-the-art facilities in several locations, perhaps the premier tuberculosis research team in the world is to be found. And while breakthroughs come slowly in fighting this ancient disease, those who work in the Mycobacteria Research Laboratories are in a hurry. Tuberculosis, once in decline, has come roaring back around the world as HIV has spread.

Today, the MRL boasts a staff of 168. Its visionary founder, Dr. Patrick Brennan, laid the groundwork for the research group 25 years ago, intending to create an internationally recognized center for the study of pathogens that cause diseases like tuberculosis and leprosy. Brennan built his team by going after the top researchers in the field.

TB is caused by various strains of pathogens that cause often fatal diseases. While generally associated with the lungs, it can attack other parts of the body. It has been estimated that a third of the world’s population has been exposed to TB. While most cases are latent, any attack on one’s immune system can lead to an activation of the virus.

That’s what happened just as the MRL was taking shape. HIV/AIDS was sweeping through developing nations, especially in Africa; a troubling resurgence occurred in tuberculosis cases as people’s immune systems were compromised. The MRL in Fort Collins was bulking up just in time to meet this unexpected challenge.

The recruitment of Dr. Ian Orme to CSU in 1986 was to play a key role in the MRL’s evolution. Orme had been doing research on tuberculosis at the famed Trudeau Institute in New York, site of the first tuberculosis sanitorium. Orme was a natural fit with Brennan, whose focus was leprosy, a related disease. It didn’t hurt that he’d just landed a sizable (for the times) National Institutes of Health research grant.

Not long after Orme’s arrival, the funding situation changed dramatically. For years there was very little funding for TB research, since the disease was considered contained. Then, as the AIDS virus spread and TB cases spiked, the NIH began to pour money into TB research. CSU’s labs were a logical place for the dollars to be spent, since other scientists studying pathogens had joined Brennan and Orme in Fort Collins.

“Those were interesting times,” says Orme. “We recruited some people, but others just came out of the woodwork to come here. Before we knew it, there were 100 people working here.”

Over the years, nearly $100 million have been invested in the lab’s research, mostly from NIH budgets but also from the Bill & Melinda Gates Foundation, which has been targeting Third World diseases and disorders for years.

In the fight against TB, research teams may labor for years for a small step forward. But many modern discoveries either emerged directly from the CSU facilities or were discovered in collaborative research work involving CSU researchers.

This year, the MRL announced that it had participated in the development of a new drug to be used against strains of tuberculosis that resist existing drugs. Orme’s team tested a drug called bedaquiline, discovered by researchers with Johnson & Johnson, in 2005. J&J turned to the MRL scientists to help it prepare bedaquiline for the Federal Drug Administration approval process. Orme’s researchers determined the drug to be “very potent.”

To give some perspective to the significance of the discovery, bedaquiline is the first new tuberculosis drug approved by the FDA in 40 years, CSU reports.

Orme is rightfully proud that the MRL contributed to the drug’s emergence, because increasingly people with TB are treated with multiple drugs — and now strains have evolved that even the combination of drugs can’t contain.

“The action by the FDA follows the results of new clinical trials of bedaquiline that have recently shown that the drug significantly reduces the duration of treatment of multidrug-resistant tuberculosis in patients, thus confirming the results of our studies performed at CSU,” Orme said.

Other breakthroughs to come out of MRL include the 2011 discovery of an enzyme that is critical to the survival and replication of the bacterial pathogen that causes tuberculosis; and the 2012 identification of components of the tuberculosis cell “envelope” that protects those cells from the drugs designed to kill them. Both were considered important contributions in the battle to defeat TB.

Today, the guard is changing at the MRL. Brennan retired last year, although he can still be found around the labs. Orme is also close to retirement. But the MRL is now studded with the top researchers in the field. Faculty member Dr. Anne Lenaerts (who Orme calls “a true superstar”) works directly with Orme and has taken on much of what was once the scope of his job. Dr. Angelo Izzo and Dr. Mercedes Gonzalez-Juarrero oversee their own programs in the MRL, and many graduate students from Orme’s programs have pursued successful research careers within and outside CSU.

Meantime, the lab has established myriad collaborations with other research centers around the world, with researchers from India and South Africa to England and France sharing personnel and information with the MRL team. The MRL is currently part of a TB fighting team addressing an outbreak of the disease among Chinese-Americans in San Francisco.

Orme also will soon have a first-hand look at a TB hotspot, as his team plans to visit a mining community outside of Pretoria, South Africa, in March. There, miners are reporting a high incidence of resistant TB. Orme wants to see the sufferers on location, to try to learn more about how a group of scientists in the foothills of the Rockies can rein in an ancient disease that continues to defy eradication.

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