art by Matthew Stoss
Old Disease, New Tricks: Targeting Tuberculosis
by Samantha Grimes
An Old Disease
Modern outbreaks of deadly, exotic viruses like Ebola and Zika have drawn newfound attention to infectious diseases. However, there are some agents that have haunted humans since antiquity. In the 19th and early 20th century, tuberculosis was one of the leading killers in industrialized countries around the world. Despite substantial advances in medicine and public health, the ailment still leads to the deaths of 1.5 million people every year.
In actuality, tuberculosis far predates the industrialized world as demonstrated by a 2003 report on the discovery of DNA from Mycobacterium tuberculosis, the bacteria the responsible for tuberculosis infection, in at least 25 out of 85 samples of mummies dated between 2050 and 1650 BCE! These findings, in conjunction with additional skeletal and mummified remains discovered in ancient Egypt, Greece and Rome, suggest that tuberculosis appears to have been not only present, but also prevalent in ancient populations.
In a Modern Age
Even though humankind has had generations of experience with tuberculosis, a disease that is now both preventable and curable, it still remains to be one of the top killers worldwide, especially for people living with Human Immunodeficiency Virus (HIV). One in three HIV deaths resulted from tuberculosis infection in 2015, with most rudimentary diagnostic tests used in developing nations failing to produce accurate results for individuals with HIV.
One of the most dangerous aspects of tuberculosis is the prevalence of the pathogen in the global population. More than one third of individuals in the world are infected with Mycobacterium tuberculosis, masked only by an asymptomatic condition known as latent tuberculosis. Although most of these people only have a 10 percent chance of contracting the active form in their lifetime, the risk increases significantly for those with compromised immune systems.
Since tuberculosis is preventable and treatable, it seems counterintuitive that it still ranks as a major ailment. However, diagnosis and treatment measures are often mediocre at best in developing countries. Given the high transmission potential of the bacterium through aerosolized particles, the condition must be diagnosed as quickly as possible since it can be transmitted relatively easily between family members living in close proximity. However, diagnosis can be complicated by the availability of modern DNA-based tests, which are simply too expensive for widespread use in the developing world.
As a result, many countries still rely on a microscope-based test to diagnose patients with tuberculosis. These methods, however, are usually only 60 percent accurate, a metric that can drop to as low as 20 percent for patients infected with HIV as they often do not have enough bacteria in their sputum to register under a microscope, triggering a false-negative result. Compounding this issue, the stigma surrounding people living with HIV often results in patients failing to disclose that they house the virus when being tested for tuberculosis, leaving doctors unaware of potential misdiagnoses.
As a way of finding more effective and affordable methods to diagnose tuberculosis, Belgian scientist Bart Weetjens opened a clinic in Tanzania that uses the curious abilities of African giant pouched rats to sniff out infected samples.
With a highly sensitive sense of smell, the animals were formerly used to detect landmines in the country. Weetjens retrained many of the rats to identify tuberculosis through its distinctive smell in a program known as APOPO, an acronym translated from Dutch that stands for “Anti-Personnel Landmines Detection Product Development.” Upon completion of their training, these rats have upwards of 73 percent accuracy in identifying a patient sample positive for tuberculosis. While the team has faced skepticism from the medical community for a somewhat unorthodox technique, their efforts have increased the detection rate of tuberculosis by 40 percent in Tanzania since the program began in 2007.
The APOPO team is not the only group with a novel development in diagnosing tuberculosis. Also acknowledging the challenges faced by developing countries, a team from Stanford University announced in February 2016 that they have created a blood test for tuberculosis with an accuracy of 86 percent, regardless of whether the patient is HIV positive or not. Known as the Khatri test, this new method of diagnosis can be run by a solar powered Polymerase Chain Reaction (PCR) machine – perfect for working in remote locations – and removes the need to collect sputum, which patients might not be able to produce on command. Likewise, in the early stages of tuberculosis or during recovery, when patients may not produce sputum, the blood-based measurement may allow better tracking of individual disease progression. The team hopes this new blood test will offer more inexpensive alternatives to diagnosing tuberculosis in the field and further help researchers analyze the effectiveness of different treatments in clinical trials.
When it comes to treating tuberculosis, current methods tend to be expensive. New drugs on the market, like Delamanid, cost approximately $1700 per dose. Such high prices for necessary antibiotics can often serve as impassable barriers for developing countries striving to provide sufficient care to patients suffering from tuberculosis. Management of the ailment is complicated even further by the increase in the number of cases of multidrug-resistant tuberculosis (MDR-TB). In 2014, 480,000 of the 9.6 million new cases of tuberculosis were multidrug-resistant, a number that has grown substantially in the last two decades. Treatment costs can rise exponentially in these scenarios, with prices running as high as $240,000 per patient right here at home in the United States. In developing countries, on the other hand, MDR-TB is a death sentence.
Fortunately, new methods of combating tuberculosis are being developed. A research team, led by Dr. Luke Guddat, has discovered an enzyme in one of the metabolic pathways of Mycobacterium tuberculosis that is used to produce three key amino acids necessary for the bacterium to survive. Since this metabolic pathway is not found in animals, researchers are hoping to engineer specific compounds to attack this enzyme directly in order to treat both MDR-TB as well as regular tuberculosis without adverse affects to the humans hosting the bacterium.
With ancient diseases, there will be no simple, clear-cut method of eliminating them completely. In order to combat ailments like tuberculosis, which has killed humans throughout our history, modern medicine must rely on a combination of approaches for diagnosis and treatment, utilizing local resources and collaborating globally in order to end one of the top ten killers in the world today.
Tuberculosis has been a deadly part of human history, but now, it seems its reign may be coming to an end.