Photo by Dean Dixon Inflammation is a series of biochemical and cellular events that constitute our body’s response to infection. Inflammatory cells surround invading pathogens and generate highly reactive and toxic chemicals including Clorox (sodium hypochlorite) and chlorine gas. They also synthesize antibodies to help clear bacteria, viruses, and other noxious stimuli, and they produce a range of signaling molecules such as prostaglandins and cytokines to amplify the inflammatory response.
This vigorous attack causes some collateral damage to surrounding tissue but normally it is local and transient. However, prolonged exposure to inflammatory stimuli or incorrect regulation of the inflammatory response leads to chronic and occasionally systemic tissue damage. As outlined elsewhere in this issue, this contributes to many important human diseases.
There is a rich history of research on the cause and treatment of inflammation, which illustrates the role that trained observation, serendipity, initiative, and hard work play in science and medicine. Some very interesting personalities have devoted their lives to inflammation research and their discoveries have had enormous impact on human health.
Drugs that treat inflammation are among the most prescribed therapeutic agents, and pharmaceutical companies spend billions of dollars trying to improve them. The complexity of the inflammatory response offers many potential strategies and targets for new drug development. So this is a very exciting and rewarding area for research.
The hallmarks of inflammation—pain, swelling, redness, and heat—and methods for its treatment were documented over 3,000 years ago. The Ebers Papyrus (1534 B.C.) describes the use of an infusion of dried myrtle for rheumatic and back pain. Hippocrates of Kos (400 B.C.) recommended a tea extract from the bark of the willow tree for pain and fever.
In 1763, an English clergyman, the Rev. Edward Stone, reported in a letter to the Royal Society, Britain’s national academy of science, that powdered willow bark administered in water is effective in reducing fever in a clinical study of 50 of his parishioners. A major component of these plant extracts, called salicin, was isolated in 1828 by the German chemist, Johannes Buchner. Salicin is converted to salicylic acid, which is the actual anti-inflammatory agent.
A small German dye company founded by Friedrich Bayer developed an industrial scale synthesis of salicylic acid in the late 1800s, but it was too harsh on the mouth and stomach to be very useful as a drug. A chemist at Bayer, Felix Hoffman, added an acetyl group to form acetylsalicylic acid (i.e., aspirin) and with a pharmacologist, Heinrich Dresser, found that it had promising anti-inflammatory activity. Bayer began marketing aspirin as a drug in 1899 and it became available over the counter in 1915. The synthesis and marketing of aspirin is viewed by many as the birth of the modern pharmaceutical industry.
In the mid-1960s, John Vane was a British pharmacologist studying the mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin. He was particularly interested in the effect of NSAIDs on the production of prostaglandins.
Prostaglandins were first discovered in 1930 as muscle-contracting components of human semen by the American gynecologists, Ralph Kurzrok and Charles Lieb. Nearly 30 years later, the structures of prostaglandins were elucidated by the Swedish biochemists, Sune Bergstrom and Bengt Samuelsson, and it was discovered that prostaglandins are made in many parts of the body including inflamed tissues.
Vane noticed that prostaglandins caused some of the symptoms of inflammation and that NSAIDs inhibited those symptoms. He hypothesized that anti-inflammatory drugs inhibit the production of prostaglandins, designed a set of experiments to test this, and in 1971 published results that demonstrated it was true. These straightforward biochemical experiments defined the basis for the treatment of inflammation by a class of drugs that had been known for millennia. For their discoveries, Vane, Bergstrom and Samuelsson were awarded the Nobel Prize in medicine in 1982.
Vane’s discovery provided a rapid test-tube screen for new anti-inflammatory drugs and many began to emerge from pharmaceutical companies. Although they were more potent than aspirin, their safety wasn’t much better. All NSAIDs cause stomach toxicity in a significant fraction of people who take them. This is due to their ability to reduce prostaglandin production by inhibiting the enzyme, cyclooxygenase, abbreviated COX.
Since the mechanism of their anti-inflammatory activity and their gastrointestinal toxicity is the same, there didn’t appear to be much one could do to reduce NSAID side effects. But Philip Needleman and Michael Holtzman from Washington University provided evidence for the existence of a second COX enzyme, and in 1991, Dan Simmons at Harvard and Harvey Herschman at UCLA simultaneously identified the new gene—COX-2.
COX-2 was found to be expressed in stimulated inflammatory cells but not in the stomach, whereas COX-1 was found in stomach and many other tissues. This suggested that COX-2 might be the target for the anti-inflammatory action of NSAIDs, whereas COX-1 might be the target for their toxicity. So the race was on to develop a selective COX-2 inhibitor!
Eight years and $200 million later, Monsanto brought Celebrex to market. Celebrex was the biggest drug launch in history, selling approximately $1.5 billon in its first year. Merck marketed Vioxx six months later, and the sales of these two blockbusters grew to nearly $6 billion annually. These selective COX-2 inhibitors appear to have an improved gastrointestinal safety profile for individuals who cannot tolerate non-selective NSAIDs, but their utility for individuals who are not highly sensitive to NSAID toxicity is the subject of considerable debate.
In September 2004, Merck pulled Vioxx off the market after finding that patients in a long-term study who took the drug had an increased risk of heart attack and stroke. Some experts believe all COX-2 inhibitors can cause cardiovascular problems in certain groups of patients. So it will be important to determine the cardiovascular risks of other COX-2 inhibitors and define the patient populations that should or should not be taking these drugs.
Studies of inflammation and treatments for it represent a classic example of the bi-directional translation of scientific discovery, from clinic to bench top and back again. Physicians, molecular biologists, pharmacologists, biochemists, and chemists focus on different aspects of how inflammation arises, what are the important molecular players, how their production can be minimized, and how one can optimize the structure of drugs that do this.
Scientists from all over the world bring their skills to this effort individually or collectively as part of multi-investigator teams. By focusing on the key events in inflammation, scientists can identify the most important studies to be conducted, and they can be assured that the results will have important clinical implications. This makes research in inflammation very exciting because one can see the impact of one’s scientific discoveries on improved human health. Since inflammation contributes to many chronic diseases, this impact is further magnified.
The pace of scientific investigation is accelerating dramatically thanks in part to the development of new tools and technologies, which enable us to plan and conduct experiments that were unthinkable only a few years earlier. Information exchange is nearly immediate via the Internet, so the most exciting findings are communicated rapidly to investigators worldwide. But the basic currency of science remains—the formulation of good ideas and the design of experiments to test them, coupled with the hard work and diligence to complete them.
Good scientists are also good innovators. They not only think about what their experimental results mean but they also ask how they can use the new findings to do something that has never been done before. This means they are frequently traveling in uncharted territory, which is simultaneously terrifying and exhilarating. It is also essential to the translation of good science into better medicine.