Since the mechanism of action of acetylsalicylic acid (ASA) was elucidated by British pharmacologist Professor Sir John Vane in the early1970s (for which he was awarded the Nobel Prize for Medicine in 1982), the active ingredient of aspirin has consistently been the focus of researchers' attention. It was thus that Taiwanese molecular biologist Dr. Min-Jean Yin of the University of Texas in Dallas (USA) came to discover that the "drug of the century" has another mechanism of action which actually takes effect inside the cell. For this she was awarded the Bayer AG-sponsored "Young Researchers' Aspirin Award" in Leverkusen on December 4, 1999, which she shared with German biologist Stefanie Oberle from the University of Halle/Wittenberg.

Nobel Prize winner Sir John Vane discovered in 1971 that acetylsalicylic acid (ASA) inhibits the biosynthesis of certain messenger molecules known as prostaglandins. These prostaglandins perform a number of different functions in the body. They play a particularly important role in the processes of pain and inflammation, in which they act as mediators. They are formed whenever a cell is damaged or even destroyed by factors such as mechanical effects, heat or aggressive chemicals. When damage such as this occurs, the fatty acid arachidonic acid is released from the cell membrane. Prostaglandins are immediately synthesized from this substance with the aid of two enzymes. ASA inhibits the activity of both of these enzymes, thus preventing the biosynthesis of pain-exacerbating and pro-inflammatory prostaglandins.

Thanks to the incredible advances made in molecular and cell biology, we now know that there are also certain mechanisms which act inside the cell to promote pain and inflammation. The transcription factor NF-kappa-B (NF = nucleus factor) plays an important role in this. Under normal circumstances, this factor, which is made up of two protein molecules (p50 and p65), lies dormant inside the cytoplasm, where it "waits" to be activated so it can go about its job. For this it has to enter the cell nucleus (hence "nucleus factor"), where it stimulates very specific genes in the deoxyribonucleic acid (DNA) to copy their "assembly instructions" for specific proteins to a close relative of DNA, ribonucleic acid (RNA), in a process known as "transcription". It is then the role of RNA to transport these instructions from the cell nucleus to the ribosomes, the "protein factories" of the cell, where the proteins specified in the genetic instructions are synthesized.

This whole process is triggered by the transcription factor NF-kappa-B. However, this factor only activates a fraction of the genes we have in our DNA. These are mainly the genes which contain the assembly instructions for certain messenger substances and other molecules which enhance our perception of pain and influence the various mechanisms involved in inflammation. The messenger molecules are known as "pro-inflammatory" (= inflammation-promoting) cytokines or "chemokines" (= chemotactic cytokines), depending on their role. The role of chemokines is to "attract" as many white blood cells (the defenders of our immune system) as possible to the site of inflammation in the shortest possible time. They manage to do this because white blood cells react to the chemotactic signals these molecules emit.NF-kappa-B is also responsible for the production of certain adhesion molecules. They are formed from the walls (endothelium) which line our blood vessels. It is their role to "trap" the white blood cells as they stream past the site of inflammation. These then bind to the endothelium and move into the inflamed tissue where they carry out their various immune functions.

Researchers believe that if the transcription factor NF-kappa-B could be prevented from activating the genes involved in these processes, the inflammation, and the pain with which it is associated, would not be exacerbated. Taiwanese molecular biologist Dr. Min-Jean Yin, who works as a researcher in the USA, discovered that this is exactly the effect exerted by acetylsalicylic acid, the active ingredient of aspirin. This involved first looking at how and when the transcription factor NF-kappa-B is activated from its dormant state in the cytoplasm. It is prevented from remaining in a permanently active state by two proteins which bind to this factor to form a complex and act as a brake. These are known as inhibitor-kappa-alpha and inhibitor-kappa-beta, or Ik-alpha and Ik-beta for short. They prevent NF-kappa-B from carrying out its transcription activities by "masking" the molecular" green light" (technical term: Nucleus Localization Signal, NLS) for its breakdown in the cell nucleus. As long as these proteins are performing this role, the NF-kappa-B is on a "red light" - it stays where it is.

So what has to happen for NF-kappa-B to become active and make its way into the cell nucleus? Dr.Yin stimulated cells in a variety of ways in order to induce this process. This stimulation from outside the cell results in the activation of two enzymes known as kinases (IKK-alpha and IKK-beta) inside the cell. They launch a chemical attack on one of the two NF-kappa-B inhibitors (I-kappa-beta) - biphosphorylation - which destroys the protein. It is broken down very quickly. As a result, NF-kappa-B receives the green light to start the activity which is ultimately what causes pain. Dr. Yin performed numerous tests to demonstrate that ASA prevents one of the two kinases (IKK-beta) from releasing the NF-kappa-B brake. The transcription factor, NF-kappa-B, thus remains inactive, eliminating the whole biochemical chain reaction which it is responsible for initiating. The work of the award- winner illustrates the complexity of the process whereby a compound with quite a simple chemical structure, acetylsalicylic acid, intervenes to fight pain and inflammation. Because NF-kappa-B clearly also appears to play an important role in the development of conditions such as arthritis, asthma, cancer and AIDS, many researchers are continuing to focus their attention on this transcription factor.

Dr. Min-Jean Yin was particularly pleased to have been presented with the "Young Researchers' aspirin Award" in 1999, the year of aspirin's 100th birthday. She stressed that she would also continue to work with ASA. According to the young scientist, who has now left university to join an American biotech company, aspirin always has a few surprises in store, and she herself likes surprises.