Before the 1960s, the existence of Alpha-1 Antitrypsin Deficiency (Alpha-1) was not known to the medical profession or the public. In the early 1960s, investigators at Malmö General Hospital in the south of Sweden were using a laboratory technique known as serum protein electrophoresis (SPE), to look at a variety of disease conditions. SPE separates the proteins in serum into groups according to their movement in an electric field. Initially, it was noted that there were three major groups of serum proteins when blood was evaluated by this method. These three groups were named alpha (a), beta (b) and gamma (g), the first three letters of the Greek alphabet. The gamma group contains most of the antibody molecules of the blood, thus the term "gamma globulin." As the investigators in Malm refined their techniques, it became apparent that the alpha group of the SPE was actually made of two distinct groups, so these were named alpha1 and alpha2. Drs. Sten Eriksson and Carl-Bertil Laurell were using the SPE technique and noted that a group of patients with a strong family history of emphysema at a young age all lacked the alpha1 band of their serum proteins. They found that the alpha1 band was almost entirely made of a single protein that had been previously named "antitrypsin" because of its ability to block the action of one of the main enzymes in the digestive system, trypsin. In 1963, they published the first scientific article describing the association between familial emphysema and the deficiency of "alpha-1 antitrypsin." At approximately this same time, investigators in the United States were also evaluating emphysema in animals in a laboratory setting. In 1965, Dr. Paul Gross found that rats developed emphysema when a drop of a substance called papain was placed into their lungs. Papain, an enzyme preparation made from the sap of the papaya tree, is the active ingredient in commercial meat tenderizer powders. In Dr. Gross' studies, it only took a month for rats to develop the lung destruction characteristic of emphysema. Other investigators went on to show that the reason papain was able to cause emphysema was that it was able to destroy one particular protein in the lung, the protein elastin. Elastin gives tissues their elastic properties. In the lungs, elastin allows the air sacs to expand when breathing in, and return to their normal size when breathing out. Elastin also gives the skin and blood vessels their elastic properties. Enzymes that can destroy elastin are called, by scientific convention, elastase. It turned out that many kinds of elastase had been identified before the mid-1960s, so scientists tested each of these elastases in animals, and each was able to cause emphysema. Other types of enzymes that destroyed different kinds of tissues in the lungs were also tested, but only enzymes that could destroy elastin could cause emphysema. The problem with these studies was that human lungs are not normally exposed to these forms of elastase. So scientists were concerned the elastase in these studies might have nothing to do with the emphysema that humans develop. Then, in 1968, Dr. Aaron Janoff described a new elastase he had found within a particular kind of human white blood cell. This white blood cell was called a neutrophil, and the elastase was named human neutrophil elastase (HNE). Here was an elastase that was relevant to human beings, since neutrophils are continually carried through the lungs by the blood, and because neutrophils are the body's primary defense against acute lung infections. Dr. Janoff and his colleagues showed that HNE was very potent at causing emphysema in laboratory animals. They also showed that HNE's activity against elastin could be totally blocked by mixing in human alpha-1 antitrypsin (AAT). Dr. Janoff and his colleagues proposed that the lungs are constantly exposed to HNE by white blood cell activity in the lungs. They suggested that, in normal individuals, AAT is the primary defense against this destructive enzyme, but in individuals with a genetic deficiency of the AAT protein, the HNE can attack normal lung tissue, leading to emphysema. This group of scientists then went on to show that certain chemicals in tobacco smoke, called oxidants, could inactivate the protective function of AAT. (In fact, a single cigarette is capable of inactivating all the AAT in a normal lung.) This finding led to the suggestion that all emphysema is due to AAT deficiency in one way or another. In individuals who smoke regularly, the AAT deficiency is a functional deficiency, due to the action of tobacco smoke oxidants on AAT. In individuals with Alpha-1, the deficiency is genetic. Since individuals with Alpha-1, in general, have some circulating AAT (people with a severe deficiency usually have about 10 to 20 percent of the normal level), the combination of Alpha-1 and smoking can cause greatly increased risk of lung destruction. Approximately six years after the description of Alpha-1 as a condition that predisposes to hereditary emphysema, Dr. Harvey Sharp published the first description of liver disease of the newborn in association with Alpha-1. This so-called neonatal cirrhosis led to liver failure in several infants he described. We now know that liver disease in children can range from very mild to life-threatening, and that liver disease in adults with Alpha-1 is not uncommon.