The Good Side
of Bad Nicotine
words by Maryann Brinley / photograph by John Emerson
This regular column highlights a breakthrough made by a UMDNJ researcher that has been recognized as outstanding by the international research community. The work of Luis Ulloa, PhD, who joined the faculty of New Jersey Medical School’s Department of Surgery last year, has been called “phenomenal” and “remarkable” by investigators around the world. It’s been published in Scientific American, Nature, and Nature Medicine. One expert said, “This is one of the great stories in immunology.”
hat if there was a chemical in the brain that could control the physiological mechanisms that modulate the immune system and prevent inflammation? This would mean that a secret to all sorts of infectious and inflammatory disorders, even the ones in which an overprotective immune system causes all the unhealthy havoc — like rheumatoid arthritis, psoriasis, Crohn’s disease and the severe sepsis that is responsible for nearly 10 percent of all deaths in the U.S. each year — was right there in the brain chemistry all along. Now what if there was a natural biochemical substance in Nicotiana tabacum, or toxic tobacco, that turned this chemical switch on?
Luis Ulloa has found this universal biochemical connection. It works so fast that animal models in his lab recover from potentially deadly sepsis within 24 hours.
“The question among researchers has always been: how is the brain modulating the immune system?” Ulloa says. While other researchers tried to learn answers by starting from specific physical symptoms, Ulloa and his collaborators tackled this complicated conundrum from another direction. They’ve been at it for years. “We believe that evolution has selected the most efficient mechanisms to control inflammation and it’s our mission to study them, exploiting them for the treatment of infectious and inflammatory disorders,” Ulloa explains. So, his team has been trying to copy the biochemical path of evolution inside the body.
Studying human functioning from this evolutionary standpoint, he identified a specific agent in the brain that regulates the immune system. It is acetylcholine, the cholinergic neurotransmitter long recognized as the communicating link for neurons. The brain controls systemic inflammation via the vagus nerve, the longest cranial nerve that innervates most of the organs of the body. Acetylcholine, the principal neurotransmitter of the vagus nerve, modulates the activation of immune cells. “Everybody knew acetylcholine as a mediator between neurons but this molecule was very important at the beginning of time. During evolution, our bodies needed these neurons to communicate with the immune cells. So what better mediator? Evolution selected this same molecule to coordinate these systems.” Looking at acetylcholine as an immune regulator and the anti-inflammatory key, “We believe we have found something very different. We are at an exciting moment studying its anti-inflammatory mechanisms and potential clinical applications.”
About the only thing that makes him slightly uncomfortable is that a vehicle to his important discovery involves nicotine, a poisonous chemical. After all, this is the same addictive substance found in cigarettes, which cause hundreds of thousands of deaths annually. Just a little drip of pure nicotine can kill a small animal. For years, it was used as an agricultural insecticide. And the small amount in cigarettes will go straight to nicotine receptors in the brain, and set up all sorts of new and embedded altered chemical signaling.
As Ulloa is quick to point out, “I don’t really like nicotine, not just because it’s toxic but the word itself rings all the wrong bells. We have been studying nicotine as a pure chemical compound with some very specific effects because it taps into the body’s own potent anti-inflammatory mechanisms.” Ulloa hasn’t been alone on this pharmaceutically-inspired nicotine trail. Studies and clinical trials exploring nicotine for everything from curing ulcerative colitis to improving memory function have been going on. Yet, the clinical use of nicotine has always been fraught with limitations because of toxic side effects.
However, Ulloa’s team has now moved beyond simple nicotine to identify alpha 7 nicotinic acetylcholine receptor (alpha 7nChR) as the specific receptor that holds the greatest clinical potential. In his lab experiments, alpha 7nChR has been shown to stop the immune cells from sending out the pro-inflammatory chemical messengers known as cytokines. These cytokines are released by the immune system after a trauma or infection, but in some cases, they end up in overdrive attacking organ systems, causing autoimmune diseases, and sending the traumatically injured into states of shock and sepsis. “It’s your own immune response becoming so strong that it can kill you,” Ulloa says.
The good news about the specific alpha 7nChR-agonists is that they can stop this cascade of symptoms right away. And they won’t cross the blood-brain barrier — a fact that disappointed researchers who were interested in Alzheimer’s or Parkinson’s cures. For Ulloa, this was important because any substance that travels to the brain can have unintentional neurological and systemic side effects he’d like to avoid. For use against infection, inflammation, and the hemorrhaging that can instigate sepsis, the alpha 7nChR is so very “interesting,” he says, in what is a profound understatement. Even the U.S. Department of Defense has been alerted to his discovery.
At a meeting in San Diego not so long ago, Ulloa was approached by a representative of the U.S. Army. “They want to control hemorrhaging in soldiers injured during combat.” If the inflammatory response set in motion by loss of blood can be delayed, more victims can make it safely to a medical center for treatment. Ulloa believes that adding a good anti-inflammatory compound like the alpha 7nChR-agonists to the resuscitation fluids given to injured soldiers during battle will be the answer.
“This is where we are now,” he explains. “We are studying the mechanism and designing novel clinical strategies for hemorrhage.” Though he hopes to move into clinical trials within the next year, there are steps yet to be taken.
A good example of basic science moving into the clinical arena, this discovery is the result of years of effort in the lab, lots of collaboration with other researchers, and an inspiring childhood experience.
“My grandma was very ill for more than a year when I was little,” he recalls. He loved her very much but hated to visit her in that hospital. Just being inside the building would make him feel physically ill. “I wanted to do something for her, to make her better, but I knew I didn’t ever want to become a physician who treated patients in a hospital setting. Now, it’s a little different,” he says laughing. “But that’s when I decided to do something in medicine, just not inside a hospital.”
Luis Ulloa began his educational journey back in Granada, Spain. He started his research with the Nobel Prize winner Severo Ochoa at the University of Madrid and earned his PhD in 1996, before coming to America to follow his passion for basic translational medical research at Sloan Kettering in New York City. Last year, Edwin Deitch, MD, NJMS chair of the Department of Surgery, lured him away from North Shore University Hospital and The Feinstein Institute for Medical Research on Long Island. Ulloa is currently funded by the American Heart Association and the U.S. Army Medical Research and Materiel Command.