BOSTON - Leo Otterbein, PhD, a scientist in the Division of Transplantation at Beth Israel Deaconess Medical Center (BIDMC) whose novel research has revealed medical applications for carbon monoxide gas, has been awarded a $1.4 million, four-year EUREKA grant from the National Institutes of Health (NIH). The award will enable Otterbein to continue to study the underlying biology behind this seemingly paradoxical idea and, if successful, could lead to new therapies for a range of medical applications from adjunct cancer treatments to fighting bacterial infections to helping kidney-transplant patients avoid organ rejection.
An acronym for Exceptional, Unconventional Research Enabling Knowledge Acceleration, EUREKA grants are part of an initiative unveiled last year by the NIH to fund innovative research and test new, unconventional ideas. "EUREKA awards reflect the NIH's continued commitment to funding transformative research, even if it carries more than the usual degree of scientific risk," noted NIH Director Francis S. Collins, MD, PhD. "The grants seek to elicit those 'eureka moments' when scientists make major theoretical or technical advances."
Although carbon monoxide (CO) has a reputation as a sinister, silent killer, it is also vital to our health and well-being. Every cell in the human body produces and uses CO gas molecules to respond to intracellular stresses, inflammation, control of blood pressure, memory and circadian rhythm. In fact, when a person gets sick, the body's CO levels protectively rise in response, the theory being that endogenous CO generation within the body is beneficial.
"Perception of CO has been a huge problem with this work," explains Otterbein, who is also an Associate Professor of Surgery at Harvard Medical School and a member of BIDMC's Transplant Institute. "It's one of the things we had working against us when we started this research, but it also helped us win this [EUREKA] funding precisely because our work is so unconventional."
Otterbein has spent the past 10 years investigating ways to harness the therapeutic powers of carbon monoxide. With this EUREKA grant, he and his colleague Barbara Wegiel, PhD, an Instructor in BIDMC's Department of Surgery, hope to change current scientific thinking and create new avenues of research on the medical benefits of low-dose CO exposure.
"We know that in normal cells, an army of proteins called 'DNA repair enzymes' patrol a cell's DNA for potential mutations," explains Otterbein. "We think that CO modulates the activity of these proteins." The key to the process appears to lie in CO's attraction to metals contained within a cell's DNA.
"In a cell that has damaged DNA mutations, extra metals congregate at the mutated areas, which, in turn, attracts more CO," he notes. "Our theory is that if there are multiple mutations - meaning CO is bound in many locations -- the CO may instruct the cell to die. If there are only mild mutations, the CO may instead communicate that the DNA is repairable and direct it to be fixed. We think that the CO helps regulate the activity of DNA repair enzymes to save the cell where possible, and that this is an ongoing physiological process that we can exploit."
One area in which CO is proving to be therapeutically beneficial is in speeding recovery and preventing organ rejection in kidney transplant patients. In 2004, Otterbein teamed up with Douglas Hanto, MD, PhD, Chief of BIDMC's Division of Transplantation and Lewis Thomas Professor of Surgery at Harvard Medical School, to test the use of low-dose CO therapy to help improve kidney function after transplantation in pigs. Animals that received CO during transplant surgery had restoration of normal kidney function in half the typical time - two to three days compared with five to seven days. Human clinical trials have begun as a result of the favorable animal studies.
"At the time of the first incision, an anesthesiologist administers a therapeutic dose of CO, which is inhaled throughout the surgery," explains Otterbein, adding that the CO dosage is 50 to 100 times lower than a toxic dose, comparable to smoking two cigarettes or standing on a street corner in the summer for five minutes during heavy traffic.
"Because of the large and increasing shortage in organs [for transplantation], transplant surgeons have been using organs that are more subject to preservation injury and poor function after transplant," explains Hanto. "Based on our animal studies, we believe that low-dose CO is safe and will result in improved organ function after transplant. We're very excited about the possibilities in a field where there have been few recent advances."
Beyond transplants, CO has shown promise in treating cancer in animal models; when used in combination with chemotherapy, CO amplifies the effects of chemo 1,000-fold. If this treatment proves similarly effective in humans, notes Otterbein, doctors could treat cancers with much lower doses of chemotherapy than is currently being used, sparing patients some of the drugs' debilitating side effects.
CO also shows promise in efficiently eradicating bacterial infections by enhancing the bacteria-fighting abilities of a group of cells known as macrophages.
"CO heightens the responses of macrophages and enables them to destroy bacteria more quickly," notes Otterbein, who together with Beek Yoke Chin, PhD, an HMS Instructor in Surgery at BIDMC has found that in animal models, CO has successfully reduced multi-organ injury. "With this therapy, we're enhancing cell's abilities to do their jobs in overwhelming situations, such as rampant bacterial infections or sepsis."
Based on compelling preclinical data from laboratories around the globe, Otterbein believes that CO may additionally prove beneficial in treating more than two dozen other conditions, including multiple sclerosis, autoimmune diseases, diabetes, hypertension, liver failure, vascular disease, lung injuries, stroke, tuberculosis, malaria and preeclampsia.
"With this grant, we are looking for ways to utilize CO anywhere in the body where modulation of DNA's response would be beneficial," he adds. "CO befits the needs of the tissues to best reestablish homeostasis."