Fight Yeast, Heal People

Twenty years ago, HIV-positive men began falling ill with unusual fungal infections in their mouths, often the first sign of a fatal pattern of illnesses that would later be known as full-blown AIDS. The infection was caused by Candida albicans, a type of yeast commonly found in people’s digestive and urinary tracts. For most people, Candida is harmless, but it can be deadly to those with AIDS.

At the time, Aaron Mitchell was busy studying the genetic mechanisms of a similar yeast, Saccharomyces cerevisiae, also known as baker’s yeast. But as the AIDS crisis snowballed, Mitchell switched to Candida.

“Every scientist has a compelling critical force that drives their research,” Mitchell explains. “I need to see the connection to infection or therapeutics.” Ever since, Mitchell, a professor of fungal pathogenesis at Columbia University, has focused on the biological mechanisms of Candida.

Wide success came in 2000 when Mitchell developed a method, called the UAU1 method, to manipulate specific genes in Candida. Before Mitchell’s method, studying the genetics of Candida was especially challenging. Unlike most yeasts, Candida is a diploid organism, meaning it has two copies of genetic code in each cell rather than just one. In order to disrupt a gene and see its effect on Candida, a scientist must successfully alter both copies of the same gene, a much more difficult process than altering only one.

“Candida needed special tricks,” says Michael Snyder, director of the Yale University Center for Proteomics and Genomics, who has known Mitchell for twenty years. “Aaron set up a very efficient method of knocking out genes in Candida.” Now everyone uses this approach, according to Snyder. Mitchell’s method is named for the piece of genetic code, UAU1, that he inserted into the Candida cells. This method aided scientists in discovering specific genes that can make Candida infections resistant to anti-fungal drugs.

The prevalence of Candida infection has continued to grow, primarily because of the increasing number of immuno-compromised patients – not only from AIDS, but also as a side effect of organ transplants and chemotherapy. According to Mitchell, seventy percent of people have antibodies against Candida, which suggests that it is exceptionally common, and usually only causes serious disease in people with weakened immune systems.

However, Candida can invade medical implants like catheters and artificial joints. On these non-biological surfaces, Candida forms huge colonies called biofilms that alter the cells’ biology and make the infection resistant to medication. Candida biofilms can cause fatal infections in healthy people with intact immune systems.

“If one of these accidental tourists happens to land on an abiotic surface, like an implant, things change,” Mitchell explains. “Once a biofilm’s formed, your doctor can treat you with as much antifungal or antibiotic they want, but you’re not going to clear the infection.”

Mitchell’s lab has recently identified proteins on Candida’s cell surface that are required to form a biofilm. Mitchell calls these proteins adhesins. “Because they’re surface molecules, they are outstanding therapeutic targets,” he explains. Developing compounds to inactivate adhesins could prevent biofilm formation and eliminate the threat of fatal infection, but scientists have yet to identify a lead compound to begin testing, the first step in developing adhesin-blocking drugs.

The history of Candida is an interesting example of how a microbe that was once harmless to humans has been given the opportunity to flourish and cause disease because of changes in modern life. Twenty years ago “[Candida] wasn’t important, and it wasn’t interesting,” says Mitchell.

Other organisms such as the bacteria Helicobacter pylori, linked to the formation of stomach ulcers, have followed similar patterns. Mitchell says he believes the increasing ability to find opportunistic links between microbes and disease will revolutionize the way the medical community thinks about disease origins. “The only better time than now to be working in this field is tomorrow,” he says.