O'TooleLab

Welcome to the O'Toole lab at the Geisel School of Medicine at Dartmouth and Dartmouth College!

The goal of this part of the website is to let the general public and non-biologists know a little more about the work we do in our lab, and how this research impacts you.

What we do. My lab studies bacterial biofilms. Bacterial biofilms are communities of microorganisms (a very small life-form sometimes referred to as “germs”). These biofilm communities typically grow attached to some sort of surface. Every day examples of biofilms include plaque on your teeth, that green stuff growing on the walls of your fish tank, and the slime that makes stones in a river or lake slippery.

My lab studies two microbes.

We study a microorganism called Pseudomonas aeruginosa. This microbe attaches to surfaces that include medical implants, like catheters, contact lenses and artificial joints. The ability to attach to these medical implants causes a number of problems. Sometimes, the microbe can clog a catheter or physically damage an implant. Also, for reasons that are not well understood, these biofilm communities are very resistant to antibiotics - this high resistance means that once the bacteria attach to a medical implant, it is impossible to take enough antibiotics to cure the infection. Thus, the only way to treat these biofilm infections is to remove the implant, which causes a great deal of trauma to the patient, extends hospital stays and increases health care costs. Finally, if the implant becomes contaminated and that contamination goes undetected, the bacteria on the implants can detach and spread around the body, causing additional infections. Some biofilms also form directly on tissues - probably the most common biofilm infection is otitis media, better known as “ear ache”.

A false colored, high magnification image of Pseudomonas aeruginosa.
The bacteria are yellow and the plastic surface they are attached to is shown in blue.

The microbes we study do not typically make healthy people ill, instead, these bacteria cause disease in patients who already have a medical condition or whose immune system is damaged. For example, Pseudomonas aeruginosa can cause infections in people suffering from burns, eye injuries and in the lungs of those patients with the genetic disease Cystic Fibrosis. My lab, working with many colleagues here at Dartmouth and across the country and world, are trying to understand how and why this microbe is so good at causing infections in these patients.

We also study a cousin of Pseudomonas aeruginosa called Pseudomonas fluorescens. We originally started studying P. fluorescens because when this microbe colonizes the roots of plants like tomatoes, it can help protect the plant from disease-causing microbes in the soil. So, P. fluorescens is a “good guy” and can help naturally keep vegetable crops healthy without using pesticides. To our surprise, we learned that the proteins P. fluorescens makes to attach to plant roots are also made by bacteria that cause diseases like cholera, Legionnaires' disease and whooping cough. So by studying this “good guy” we've also learned more about how disease-causing organisms work - this is just one example of how basic research can often make unexpected discoveries.

This image shows *P. fluorescens* (in green and indicated by the arrows) growing on the roots of a tomato plant.

What we hope to accomplish with our research, and how this impacts you. Ultimately, we hope that by better understanding how biofilms colonize medical implants, we can figure out better ways to prevent these communities from forming. New anti-biofilm treatments would reduce infections associated with medical implants, lessen hospital stays and lower health care costs. Or in some cases, we actually want to control how and when such biofilms form, for example, biofilms play a positive role in waste water treatment facilities to help clean up sewage and are used to manufacture important chemicals and foods.

We also want to better understand how to treat these biofilm infections once they form, without having to resort to removing the medical implant from patients and to reduce the burden of disease.

Currently, my lab has several ongoing projects. We are exploring the genes and proteins of bacteria that make biofilms, to better understand how these microbes work. We are also developing new therapies to treat biofilms in the lungs of cystic fibrosis patients, and developing new coatings and compounds to block the formation of biofilms on medical implants. We are also working on a new class of antibiotics.

Let me highlight one example of how our work has helped patients. Catheter-based infections cost ~$1B dollars annually in the US, largely due to increased hospital stays and additional treatment burden. One particularly hard-hit population is those individuals that require hemodialysis due to loss of kidney function. Until they receive a transplant, these patients carry an implanted catheter that is subjected to repeated colonization by bacteria and subsequent systemic infections. Between dialysis treatments, the catheter is filled with a “lock solution” to prevent blood from coagulating. A recent article in Renal and Urology News highlighted a clinical study showing that sodium citrate works better than the commonly used heparin as a catheter lock solution in hemodialysis patients. The study, published in the American Journal of Health-System Pharmacy by Yon and Low, both clinical nephrology pharmacists in the Veterans Affairs San Diego Healthcare System, was based in part on a series of studies led by Robert Shanks Ph.D., a post-doctoral fellow in my lab and in collaboration with Martha Graber M.D., a nephrologist at the Dartmouth-Hitchcock Medical Center. Dr. Shanks is now an Associate Professor at the University of Pittsburgh. Our studies compared the impact of various catheter lock solutions on biofilm formation by Staphylococcus aureus and S. epidermidis, two bacteria that commonly colonize and infect catheter lines. In a paper we published in 2005, we showed that heparin actually stimulates biofilm formation by S. aureus on catheter-like material, likely increasing the rate of infection in patients. A subsequent study in 2006 in Nephrology Dialysis Transplantation showed that sodium citrate at concentrations above 0.5% efficiently inhibits biofilm formation and cell growth of S. aureus and S. epidermidis, and for those organisms most typically associated with these infections, low levels of citrate did not promote biofilm formation. Together, these studies strongly suggested that a switch from heparin to sodium citrate might reduce infections in patients on dialysis. The recent publication in American Journal of Health-System Pharmacy indeed confirmed this idea in a study of 60 hemodialysis patients, which showed a reduction in infection from 33% in patients using heparin to 19% of patients using citrate as a catheter lock solution. Thus, the studies in the lab have had a positive impact on reducing infections in patients.

In addition to our research, my lab works to train the next generation of scientists and medical doctors. Members of my research group have gone onto teach at colleges and universities, work in the biotechnology industry, study how to produce biofuels, research new ways to treat malaria and have received their M.D. degree and currently treat patients. We also work closely with physicians who both treat patients and do research. Working together, we have a better chance of achieving our ultimate goals of improving anti-biofilm treatments, and better understanding how microbes impact our health and disease.

How you help. Current and past funding for the work we do comes from several sources, including the federal government through the National Institutes of Health (NIH) and National Science Foundation (NSF), through private foundations, like the Cystic Fibrosis Foundation, The Pew Charitable Trusts and the Gates Foundation, and from industry and biotechnology companies.

Funding from the NIH and NSF comes, ultimately, from the American people. So everyone in America helps to support research, and as a result, the U.S. is the world leader in research and innovation. We take very seriously our commitment to use all of our funding responsibly and efficiently.