As the first of five children in her working-class family, everything Brenda Wilson knew about scientists came from watching them on television or reading in books. Now theme leader for the Host-Microbe Systems research group at the new Institute for Genomic Biology, Wilson's story is no less fascinating than those she saw growing up.
“I always liked the idea of being a scientist and a professor, though my idea of what that involved was very naïve,” said Wilson, associate professor of microbiology who has been on the faculty since the fall of 1999. “I had this idea it was like what you see in the movies, where brilliant people discover new things, spinning off brilliant insights every hour. Of course it’s a lot slower than that, and a lot more work than that!”
Wilson excelled in math and chemistry at her rural Arkansas high school. She was on her own in terms of how to realize her dreams, but that was not a problem for her.
“My philosophy has always been to start at the top and work my way down,” said Wilson with a grin and a shrug.
Wilson applied to five top colleges and took the best offer, which was a full scholarship at Barnard College in New York City. Majoring in both biochemistry and German (Wilson’s mother is German) and minoring in chemistry, Wilson threw herself into her college coursework. When it came to graduate school, Wilson started at the top again. Her best offer came from the chemistry department at Johns Hopkins, where her thesis project was focused on antibiotic biosynthesis, including peptide synthesis and protein chemistry. This suited Wilson’s goal, which was to better understand basic, mechanistic cell processes in order to fully investigate biological questions down the road.
“I like when I can see how something works, and not just memorize facts,” said Wilson.
In the 1980s, when Wilson was completing her doctorate and considering postdoctoral positions, academic research in antibiotics was virtually nonexistent.
“Academia couldn’t compete with pharmaceutical companies, so I looked around to see what else I was interested in,” said Wilson. “I wanted it to be helpful, of course.”
Wilson decided to investigate the field of bacterial protein toxins and ways to combat them by developing antitoxins.
“Until recently, people were not all that aware of toxin-mediated diseases and how bad they are,” said Wilson. “Now, because of the anthrax scare, everyone realizes we have very few tools to battle toxin-mediated diseases.”
There are two ways to combat toxins, one is to vaccinate a given population against a particular toxin and the other is to develop an antitoxin that works after an individual is exposed.
In the late 1980s, researchers were just beginning to understand the mechanics of how classic toxins, like diphtheria and cholera, work. So Wilson signed on as a postdoctoral fellow with John Collier at Harvard University, the so-called “king of bacterial toxins.” The laboratory was looking at the structure, function, and mode of action of bacterial toxins with the idea to make better recombinant vaccines. Wilson spent much of her postdoctoral studies figuring out how toxins, particularly the diphtheria toxin, worked.
However, as debilitating as toxin-mediated disease is, it only affects a small number of people. For example, there might be 300 botulism cases per year. As Wilson knew from her antibiotic work, pharmaceutical companies are not motivated to develop a vaccine with such a small market.
The other approach, and one Wilson was interested in even as a postdoctoral fellow, was to treat victims post-exposure. The hurdle with this approach is getting the antitoxin inside the cell, where the toxin is doing its dirty work. Current antitoxins, which are based on antibodies, cannot do this. This means that even once a patient gets the antitoxin treatment it takes weeks for the toxin already in the cells to clear from the body and for the patient to recover. For example, in the case of botulism, which causes paralysis via the botulinum neurotoxin produced by Clostridium, patients must be on a ventilator to breathe. In addition, the antitoxin serum cannot reverse the paralysis, so although nerves can regenerate, recovery is slow and not always complete. It typically takes months for the toxin to clear the body and months to years of physical therapy to recover.
The secret, Wilson thought, was to understand how the toxin got inside the cell and use that knowledge to design a better antitoxin. Wilson has spent the last three years working on developing a better botulinum neurotoxin inhibitor (to stop the action of the toxin) and to create a delivery system to get that inhibitor inside the nerve cells. She is about to test her new, improved botulism antitoxin on animal models.
After leaving Harvard for a faculty position at Wright State University, Wilson decided to expand her research to include the toxin from Pasteurella multocida.
“I got interested in this one because it almost killed me,” she said.
Like so many toxin-producing bacteria, Pasteurella multocida only becomes dangerous if the host is already immunocompromised. One day in 1989, while still a postdoc, Wilson went to a petting zoo with her son. Afterwards they both washed their hands, but it turned out Wilson had a bit of strep throat at the time. The next thing she knew, she had spent three weeks in Massachusetts General Hospital in Boston.
“I made Grand Rounds!” she said, her grin belying the severity of her illness.
Pateurella is a nasty pathogen. Before it was all over, Wilson’s eardrums had burst, blood and pus spewing from her ear. She lost her sense of balance and all hearing in her right ear. Soon the infection spread to her other ear. She got meningitis and had to have a spinal tap. The massive doses of antibiotics made Wilson’s hair fall out. Still, the antibiotics couldn’t nail the Pasteurella completely because it hides in the tonsils. Finally, Wilson was healthy enough to have a tonsillectomy. It took four months for her to completely recover; Wilson still has poor hearing in her right ear.
Coincidentally, 1989, the year Wilson had her personal wrestling match with Pasteurella, was the year that the Pasteurella toxin was first cloned and sequenced.
“It is a fascinating toxin,” said Wilson. “Pasteurella is a normal microbe found in about 60 percent of domestic animals as part of their normal flora. Its toxin has different effects, depending on the particular tissue cell it encounters. In addition, the toxin has multiple targets inside the cells and those targets are different from the target of other bacterial toxins.
“This means it is not only interesting to study, but helpful as a cell biology tool,” said Wilson.
Pasteurella toxin, Wilson has found, typically works by dampening the immune system, so that hosts end up with a chronic infection (unless, as in Wilson’s case, there is a coinfection). This chronic infection can result in detrimental long-term effects. This is why Wilson’s ultimate goal is to use the microbe’s own mechanisms (i.e., toxins) to design therapeutics. It will take a while and a lot more work, but Wilson is confident that she will prevail and that it will be worth the effort.