Weinberger realized the potential of and additional crosses are made each this specialty fruit and was responsive year. There is reason to expect a com- to the industry need for reliably tested plete replacement of present varieties. freestone varieties. A sequence of sim- Weinberger's interest in improving ilar varieties over a period as long as Japanese-type plums led to a resump- for peaches is envisioned. tion of breeding for new varieties. An As was true with peaches, main crop earlier, very productive, cooperative apricot varieties were static for many program between the USDA and the years. As a consequence, the varieties, California Agricultural Experiment mostly of European origin, became Station at Davis had developed *Bur- less well suited to changing market mosa,' 'Redheart,' 'Nubiana,' 'La- demands. Commercial drying of fruit roda,' and several other varieties which became less prevalent, and the need became important to the industry. for larger fruit and for resistance to Using these and other varieties as pit burning—browning of flesh adja- parents, Weinberger produced over cent to the pit—became more im- 17,000 hybrids and now is testing portant as more fruit was shipped fresh many promising selections. One was or canned. named 'Frontier' in 1967. It com- Weinberger realized the need for bines the high quality of the leading greater resistance to pit burning, im- red-fleshed variety with much better proved firmness, and larger size in exterior color, thus increasing its mar- varieties similar to the major varieties. ket appeal. 'Friar', an amber-fleshed In 1963, 'Gastleton' was introduced and black-skinned variety, was in- by USD A because it fulfilled these troduced in March of 1968. Other objectives. The other selections which selections are undergoing rigorous plot promise to complement this variety and commercial testing. Weinberger are in various stages of testing. Over is growing some 3,200 plum seedlings 2,100 seedlings have not yet fruited. which have not yet fruited.

Penicillin: Breakthrough to the Era of Antibiotics

FRANK H. STODOLA

To many, scientific research don in 1928. This discovery was a is an impersonal and forbidding pur- highly improbable event and involved suit. This notion is something of a two elements of luck. The right kind of myth, perhaps never more so than for mold spore had to come in contact penicillin. Its story abounds in drama with the right kind of disease germ and and human interest. thereby produce an unusual eflect. Forty years have now passed since And this eflect had to be observed by Alexander Fleming was led by a "curi- someone who knew its meaning, ous concatenation of circumstances" Fleming was such a man: A highly to the discovery of this astonishing sub- trained and acute observer who had stance at St. Mary's Hospital in Lon- devoted his whole career as a medical 339 bacteriologist to the search for nontoxic 1930, he sent a subculture of Fleming's agents for the treatment of disease. It mold to the U.S. Department of Agri- would be hard to find a better example culture's Bureau of Plant Industry at of fortune favoring the prepared mind. Beltsville, Md., to be examined by Not only did Fleming make the Charles Thom, a world authority on original observation on penicillin—he fungi, including the Penicillia. The sensed the importance of his discovery. result of this first visit of the penicillin He preserved the mold; and he care- organism to America is recorded in fully described its behayior in a paper Thom's notebook as follows : entitled "On the Antibacterial Action 5112 H. Raistrick of Cultures of Pénicillium." Beautiful Rec'd 5-14-30 in its simplicity, this paper was to 5112.1 P. rubrum (?) isolated by Fleming. become one of the classics of medical British collection No. 3127. Culture on literature. It was the opening gun in Dox-glucose agar Apr.25.30 the victorious battle against the in- = P. notatum fectious diseases. It ushered in the Era Thom's assignment of the mold to of Antibiotics and altered the whole the correct species (P. notatum) was course of modern medicine. invaluable. It identified the culture In his paper, Fleming wrote "A with a cosmopolitan series of molds certain type of pénicillium produces and, later, gave direction to the search in culture a very powerful antibacterial for more productive strains. substance. . . . The action is very Valuable contributions were made marked on the pyogenic cocci and the by the Raistrick group to the produc- diphtheria group of bacilli. . . . Pen- tion and chemistry of penicillin. Un- icillin is nontoxic to animals in enor- fortunately, the work was not con- mous doses and is nonirritant." He tinued beyond 1932 because of the suggested, "It may be an efficient anti- accidental death of the Mycologist septic for application to, or injection Charles and the departure of the into, areas infected with penicillin- Bacteriologist Lovell. Although tem- sensitive microbes." porarily discouraged by this setback, Everything of importance is in these Fleming did not lose faith in penicillin. few sentences! Yet, who would have In lectures and publications, he con- guessed what a profound effect this tinued to point out its virtues and modest account was to have upon its possibilities. human welfare. The scene next shifts from London Knowing that chemical studies on to the Sir William Dunn School of penicillin were next in order, Fleming Pathology at the University of Oxford. was pleased when Harold Raistrick of There Howard Fiorey, a medical man the London School of Hygiene and who had extensive experience with the Tropical Medicine undertook the iso- antibacterial enzyme lysozyme dis- lation of penicillin. Being a careful and covered by Fleming in 1922, joined experienced worker on the chemistry forces in 1939 with Biochemist Ernest of mold products, Raistrick took the Chain, Organic Chemist E. P. Abra- necessary first step in such work by ham, and Bacteriologist Norman Heat- establishing with certainty the identity ley in a new and determined attack on of the penicillin organism. On April 29, the penicillin problems. Aided by a $5,000 grant from the Rockefeller Foundation, they succeeded by late FRANK H. STODOLA hos been in charge of the 1940 in taming the previously intracta- Pioneering Laboratory for Microbiological Chemis- ble penicillin by converting it into a try at the Northern Utilization Research and stable, dry powder. Development Division, Agricultural Research So effective was this purified ma- Service, Peoria, III,, since 1957. He worked for Ja years before that in the Fermentation Division, terial in the treatment of some human whose members received the Lasker Award in 2946 infections that by early 1941 Fiorey for penicillin research. and his associates were convinced that 340 if penicillin could be made available molds, had succeeded, with the help in quantity, its use in the treatment of of Heatley, in increasing the Oxford war wounds would result in a marked yields tenfold by the use of corn steep physical and psychological advantage liquor, a byproduct of corn starch over the enemy. Unfortunately, it was manufacture. not possible at that time for the al- On December 17, this highly en- ready overburdened British chemical couraging result was disclosed by and drug manufacturers to undertake Robert D. Coghill, head of the Fer- large-scale production of penicillin, mentation Division at NRRL, to rep- so in July 1941 Florey and Heatley resentatives of four companies (Merck, came to this country to take advantage Squibb, Pfizer, and Lederle) at a meet- of the more favorable conditions and ing called in New York by A. N. the American knack for mass produc- Richards, a friend of Florey's, chair- tion. They were not to be disappointed. man of the Committee on Medical Their first stop was at New Haven, Research of the Office of Scientific Conn., where Florey's children had Research and Development. This meet- been staying at the home of J. F. ing established a vital link between Fulton during the bombing of London. government research at NRRL and There, R. G. Harrison, chairman of the chemical and pharmaceutical firms the National Research Council, ad- capable of large-scale production and vised the English visitors to see Thom. led to a fruitful collaboration that was He promptly recommended the newly to continue throughout the war. established Northern Regional Re- The simplest and quickest way of search Laboratory (NRRL) at Peoria, producing penicillin in quantity in 111., where USD A investiga tojs were 1941 was by the "surface" method, in already familiar with industrial fer- which the mold grows as a mat on the mentation processes and where a large top of a nutrient solution. Pilot plant collection of molds was maintained. production of penicillin by this process The following telegram on July 9 from was slow at first because of contamina- P. A. Wells, acting head of the Bureau tion and isolation problems. By March of Agricultural Chemistry and Engi- 1942, only enough penicillin was neering, to O. E. May, director of the available in the United States for the laboratory, was to set in motion a treatment of one case. series of events of utmost importance Prospects were vastly improved, to the war effort. however, when K. B. Raper, a former "Thom has introduced Heatley and collaborator of Thom, found a superior Florey of Oxford. Here to investigate strain of P. notatum-chrysogenum at pilot scale production of bacteriostatic NRRL, which doubled the yield of material from Fleming's pénicillium penicillin, raising it to 150 units per in connection with medical defense milliliter of nutrient solution com- plans. Can you arrange for shallow pared to the two units of the Oxford pan setup to establish laboratory re- group. This yield left no doubt that sults in metal?" the surface method was suitable for To which May replied the next day: mass production. Factories were built "Pan setup and organisms available here and in England that could proc- Heatley and Florey experimentation. ess in one day the culture liquor from Details of work of course unknown and 30,000 milk bottles. It was by this suggest they visit Peoria for discussion. means that almost all the penicillin Laboratory in position to cooperate used to establish its clinical usefulness immediately." was obtained. The meeting was held in Peoria on Still another means of producing July 14, and laboratory work was penicillin was available in 1941. The underway 2 days later. By Novem- mold could be grown as a suspension ber 26, 1941, Andrew J. Moyer, the in stirred and aerated tanks of nutrient laboratory expert on the nutrition of solution, as was being done in the 341 Sir Alexander Fleming, right, when he visited USDA's laboratory in Peoria, 111., the year he received the Nobel Prize for discovering penicillin. Below, Andrew J. Moyer of the Peoria lab whose steep liquor-lactose medium made possible the mass production of penicillin. commercial production of gluconic sufficient penicillin by D-day in Nor- acid. This so-called "submerged" proc- mandy in 1944 to treat all severe cas- ess offered tremendous advantages over ualties, both British and American." the surface method in reduced space And it is not amiss to add that the and labor requirements, one 10,000- American industrial success would not gallon tank being the equivalent of have been possible without the prompt 70,000 bottles. However, the Fleming and sustained support of Government organism was unproductive in tanks. administrators and research workers. It was not until strain 832 was devel- All during the war, studies on the oped at NRRL that the submerged chemistry of penicillin were actively process was assured of industrial pursued in England and in the United adoption. States. It was hoped that the makeup By 1943i^ the War Production Board of the penicillin molecule could be was convinced of the need for greatly established and that a practical syn- increased production of penicillin for thesis could be devised which would military use, and 21 submerged process give unlimited amounts of the drug plants were rushed to completion at a without recourse to fermentation. cosí of about $20 million. Through the Only the first hope was realized. Be- use of a succession of improved strains fore the war was over, the arrangement (NRRL 1951-B25, Carnegie Institu- of the carbon (C), hydrogen (H), tion X-1612, and University of Wis- oxygen (O), nitrogen (N), and sulfur consin Q-176), these factories raised (S) atoms with respect to one another the 1943 production of 28 pounds to was known and could be pictured in 14,000 pounds for the year 1945, the shorthand of the chemist as: enough to meet all military and some civilian needs. With yields of 16,000 units per milliliter, not uncommon in E—C—NH—CH—CH C(CH3)2 I I 1968, it is amusing to recall the state 0=C ^N- CH—COOH of mind of early workers, as revealed in a letter of November 24, 1941, from where R represents any of the five NRRL to the bureau chief which read different groups of atoms found in the in part: natural penicillins produced by the "Recent experiments have also indi- mold. In the common commercial cated that penicillin can be prepared penicillin G, R is CgHg—CH2—. in submerged culture with yields of 3 By 1946, the conditions of use, to 4 units per cc. This was just a dosage, and standardization of peni- preliminary experiment, and probably cillin were essentially worked out. The does not represent the ceiling for this drug was known to be remarkably type of culture." effective in the treatment of hemolytic Within 25 years, yields increased streptococcic infections, such as tonsil- more than 4,000 times. litis, scarlet fever, puerperal sepsis, It would be hard to overestimate the erysipelas, cellulitis, and wound in- contribution of penicillin to the war fections; subacute bacterial endocardi- effort through the saving of countless tis; gonorrhoea and syphilis; anthrax lives and limbs. and gangrene. And happily, mass pro- The American share in this cooper- duction had placed the lifegiving medi- ative venture was acknowledged by cine within the reach of almost every- the Oxford group as follows: one. One would have guessed that "... too high a tribute cannot be after such a hectic and precocious paid to the enterprise and energy with adolescence the "queen of drugs" had which American manufacturing firms a right to look forward to a placid tackled the large-scale production of lifetime of service. This desirable state the drug. was not to be—yet. "Had it not been for their efforts In 1945, reports began to appear there would certainly not have been that hinted of a disturbing situation. 343 With increasing frequency, new forms Penicillin V came into clinical use of the dreaded Staphylococcus aureus in 1953 and has had wide application were being encountered that did not since. But hopes that it would replace yield to the magic of penicillin. Soon penicillin G entirely were not realized these "bandit" strains were being when its range of activity proved to be spread by cross-infection to hospitals, somewhat limited. However, the suc- and by 1950, the situation was almost cess of this modified penicillin en- out of control. Distressing as it was, couraged a further search, and still it had to be admitted that the sta- better oral penicillins were later found tus of penicillin in 1950 was actually among the many semisynthetic peni- less satisfactory than it had been in cillins prepared by the workers at 1945. Fortunately, cooperative scien- the Beecham laboratories. tific research was again able to meet Another problem of great concern to the challenge in dramatic fashion. medical men is the ability of penicillin The breakthrough in the battle to produce hypersensitivity reactions, against the resistant strains came from which can vary in severity from a skin workers at Beecham Research Labora- rash to death from anaphylactic shock. tories in England, who took advantage The problem is doubly serious because of a clue supplied in 1950 by Sakaguchi no wholly satisfactory method for de- and Murao in Japan. An enzyme was termining penicillin hypersensitivity O has yet been developed. The incidence II of the reaction varies fi*om 2 to 15 found that would remove the R—C— percent, depending on the patient's group from commercial penicillin G, previous history of allergy. In 1964, leaving the "nucleus," which could it was estimated that 100 to 300 fatal easily be converted by the chemist into reactions to penicillin occur each year O in the United States. II The gravity of the situation has new penicillins with different R—C— prompted many attempts to determine groups. Hundreds of these semisyn- the cause of the reactions and to devise thetic penicillins were prepared and means of eliminating it. Only recently tested. One of them, methicillin, have promising results been obtained. proved to be remarkably effective It appears that penicillin itself is not against staphylococci resistant to peni- responsible, but rather a protein im- cillin G. Thus, the penicillins were purity. There is now some evidence restored to their former position as that this impurity can be removed to the agents of choice for treating com- give purified penicillins of greatiy im- municable infections like sore throat, proved properties with regard to hy- scarlet fever, and rheumatic fever. persensitivity. If this encouraging lead Research workers have also been works out, it will be a boon to those active in other directions, seeking to now denied penicillin's benefits. circumvent the shortcomings of peni- So, despite some limitations, peni- cillin. One of the most successful of cillin remains the most valuable of the these has been the development of the available antibiotics, with annual pro- oral penicillins to eliminate the incon- duction in the United States approach- venience of intravenous injection. The ing 2 million pounds. Its usefulness problem was to produce a stable peni- has not been limited to human therapy ; cillin that would not be destroyed by large amounts are used in veterinary stomach acids as penicillin G is. One medicine and for the promotion of of these, penicillin V, was discovered growth in animals. From humble be- in 1948 by Behrens and his associates ginnings in 1941, the production of of Eli Lilly and Go. It was produced penicillin has spread all over the by alteration of the R group in peni- world, with manufacturing facilities in cillin, through the use of the proper 27 countries. Truly a great and lasting nutrient for the mold. tribute to Fleming and his successors. 344