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The Medical Research Council Laboratory of Molecular Biology

by Max F. Perutz
1962 Nobel Laureate in Chemistry

 

Haphazard Growth

On a summer day in the late fifties a delegation from the Soviet Union appeared in Cambridge demanding to see the "Institute of Molecular Biology". When I took them to our shabby prefabricated hut in front of the University Physics Department, called Cavendish Laboratory after its nineteenth century benefactor, they went into a huddle until finally one of them asked me: "And where do you work in winter?" They wanted to know how I had planned our successful Research Unit, imagining that I had recruited an interdisciplinary team as Noah had chosen the animals for his ark: two mathematicians, two physicists, two chemists, two biochemists and two biologists, and told them to solve the atomic structure of living matter. They were disappointed that the Unit had grown haphazardly and that I left people to do what happened to interest them.

John Desmond Bernal, the discoverer of X-ray diffraction from protein crystals.

 

Proteins were Black Boxes

In 1936, when I joined J. D. Bernal's Crystallographic Laboratory as a graduate student from Vienna, it was a small, dingy sub-department of the famous Cavendish Laboratory headed by Ernest Rutherford, the discoverer of the atomic nucleus, who was regarded as the world's greatest experimental physicist. On the other hand, I was trained as a chemist, and my interests grew in another direction. It had just been discovered that all chemical reactions in living cells are catalysed by enzymes and that all enzymes are proteins. Genes were also believed to be made of proteins, but next to nothing was known about the structure of proteins, let alone their mechanism of action. They were black boxes. Protein structure therefore seemed to be the central problem of biology, and X-ray crystallography was the only method in principle capable of solving it.


Haemoglobin Enters the Scene

Haemoglobin was easily available and happened to be one of the very few proteins to have been crystallised. In an early attempt at finding something out about the species specificity of proteins, two scientists at the Carnegie Institute in Washington had published a comprehensive atlas of haemoglobin crystals of different animals (Reichert & Brown 1909). In 1937, when I began the X-ray analysis of haemoglobin crystals, so little was known about it that every morsel of structural information was a gem. The Cambridge respiratory physiologist Joseph Barcroft once remarked that all that was known about haemoglobin could be written on the back of a postage stamp. My first results showed that it was a spheroid with a well-defined atomic structure, a new concept when proteins were still widely regarded as woolly colloids, that it consisted of two identical halves which were not penetrated by diffusible electrolytes, and that its four haems were roughly parallel to each other. The problem was how to get further.

 

Two Strokes of Luck

Rutherford died in 1937, and W. L. Bragg, the founder of X-ray analysis, succeeded him as Cavendish Professor. This was a blow to the atomic physicists in the Laboratory, but extremely lucky for me. Bragg was fascinated by the idea that X-ray analysis, which he had started with the determination of the sodium and chlorine positions in common salt, might be extended to the immensely complex molecules of the living cell. When my money ran out after Hitler's annexation of my native Austria, he obtained a grant from the Rockefeller Foundation for my support which saved my scientific career. It continued until the mid-sixties and was to prove crucial for the success of our Research Unit.

Sir Lawrence Bragg, around 1965.


Towards the end of the war, Bragg recommended me for a University Lectureship, but the mills of Cambridge University grind slowly, and it took nine years to materialise. On the other hand, the Rockefeller Foundation considered that the University rather than they, should pay my salary, and I found myself out of a job. John Kendrew had joined me in 1945 and had started a comparative X-ray study of adult and foetal sheep haemoglobin, a grossly premature project for the state of X-ray analysis in those days. He had a grant for two years, but nothing after that.

From this bleak outlook we were rescued by another of Cambridge's great scientists, David Keilin, the genial, Russian-born biologist who had discovered the cytochromes and headed the Molteno Institute of Parasitology. He had given Kendrew and me bench space in his biochemistry laboratory for the preparation of our crystals and was keenly interested in all haem proteins, including haemoglobin.


Foundation of the Medical Research Unit for Molecular Biology

Keilin was friendly with Sir Edward Mellanby, the formidable head of the Medical Research Council (the British equivalent of the National Institutes of Health), and he suggested that Bragg should apply to Mellanby for support. This was duly granted in October 1947 and was the turning point in our fortunes. The Council established a "Research Unit for the Study of the Molecular Structure of Biological Systems", a mouthful which we changed later to "Molecular Biology Unit", with Kendrew and me as its founding members. The subject became a magnet for the attraction of talent. Francis Crick, Hugh Huxley and Jim Watson were among the first to join us. Vernon Ingram came from London, Sydney Brenner from Johannesburg, Paul Doty, Alex Rich, Seymour Benzer and many others from the United States. By 1956, the Unit had grown so large I spent my time scrounging for a little bench space in a butterfly museum here or the abandoned cyclotron room there, and toyed with the idea of asking the Medical Research Council to build us our own laboratory. On the other hand, though my introduction of the method of isomorphous replacement with heavy atoms had made the solution of protein structures possible in principle, none had yet been solved. Watson & Crick's mechanism of replication of DNA, though highly plausible, was still unproved; and we were too weak in biochemistry to qualify as an interdisciplinary laboratory, a concept yet to be invented.

Perutz and other members of the Medical Research Council Unit for Molecular Biology outside the hub next to the Cavendish Laboratory in Cambridge where the Unit was housed from 1956 to 1962.
Bror Strandberg and Richard Dickerson outside the hub with the output from the electronic digital computer Edsac II. The pictured tapes specified the phases of the X-ray reflections used to calculate the first atomic model of a protein; sperm whale myoglobin.

 


The Laboratory of Molecular Biology Comes into Being

That situation was transformed in 1957 when Kendrew's first low resolution structure of myoglobin emerged, when Matthew Meselson proved that each of two DNA daughter double helixes was made up of one parent strand and one newly synthesised strand, and Arthur Kornberg showed that the base sequence of the newly synthesised strand was complementary to that of the parent strand, exactly as Watson & Crick had predicted. Most important, Fred Sanger in the University Department of Biochemistry had just completed the amino acid sequence of insulin, the first sequence of a protein to be determined, and he agreed to join us.

I submitted a report on Recent Advances in Molecular Biology together with plans for the new laboratory to the Medical Research Council. When I was invited to present this to a meeting of the Council, I spent a sleepless night worrying how it would be received, but as soon as I entered the Council room, one of the members told me that it was the most interesting report he had ever read and, to my relief and delight, the Council approved our plans that same day.


John Kendrew demonstrating his model of myoglobin to the Queen at the opening of the Laboratory of Molecular Biology in May 1962.
In the back from left to right Mavis Bhow, Gisela Perutz, Lady Himsworth, Sir Harold Himsworth and Sir William Shawcross.


The Laboratory of Molecular Biology was built next to, and simultaneously with, a new hospital south of Cambridge, initially with a floor area of 22,000 sq. ft. We moved in in February 1962, and in May the Queen came to open it. Crick and Brenner stayed away because they disapproved of royalty, but Watson came specially from Harvard in order to be presented. When we proudly showed the Queen and her party the atomic models of DNA and myoglobin, one of her Ladies-in-Waiting exclaimed: "Oh, I had no idea we have all those little coloured balls inside us!"

 

It was a Merger

In business jargon the laboratory would have been called a merger, because four groups joined to bring it into being: Fred Sanger's from the Cambridge University Biochemistry Department; Kendrew's, Crick's and my groups from the Cavendish Laboratory; Aaron Klug's from Birkbeck College and Hugh Huxley (on his own) from University College, London. Cesar Milstein arrived from the Argentine to join Fred Sanger soon afterwards. The laboratory started with about thirty scientists employed by the Medical Research Council and a roughly equal number of graduate and postdoctoral students and visitors. By now it houses about a hundred scientists paid by the Medical Research Council, fifty paid from other sources and a hundred students and visitors. Initially, the Laboratory comprised three divisions: Protein and Nucleic Acid Chemistry under Sanger, Molecular Genetics under Crick and Brenner, and Structural Studies under Kendrew and me. By now, Molecular Genetics has become Cell Biology, Protein and Nucleic Acid Chemistry includes Immunology and a new Division of Neurobiology has been added. We are also closely linked to Alan Fersht's and Greg Winter's Protein Engineering Laboratory.

Perutz, Bernal and Crick at the opening of the Laboratory of Molecular Biology in May 1962. In the center the double helical model of DNA.




How the Laboratory was Governed

Since there was no difference in age or distinction between us, I persuaded the Medical Research Council to appoint me Chairman of a Governing Board rather than Director, the Board to be made up of Crick, Kendrew, Sanger and myself. This arrangement reserved major decisions of scientific policy to the Board and left their execution and financial responsibility vis-à-vis the Medical Research Council to me. The Board met only rarely when such decisions needed to be taken. This worked smoothly and left me free to pursue my own research. Seeing the Chairman standing at the laboratory bench or the X-ray tube, rather than sitting at his desk, set a good example and raised morale. The Board never directed the laboratory's research, but tried to attract, or to keep, talented young people and gave them a free hand. My job was to take an interest in their research and to make sure that they had the means to carry it out.

 

Importance of Good Technical Facilities

I was able to do this thanks to our excellent technical facilities. Shortly after the foundation of our Research Unit, Kendrew and I asked the Medical Research Council for funds to appoint an engineer, D.A.G. Broad, to design an X-ray tube with a rotating anode. His design provided us with a beam ten times stronger than the commercial tubes then available. Together with the precision cameras bought for us in America by the Rockefeller Foundation, it equipped us better than anyone else in the field and made possible the solution of the first protein structures. This early experience and also the technical facilities we enjoyed at the Cavendish Laboratory made us decide to equip our new Laboratory of Molecular Biology with large mechanical and electronic workshops for the development of new instruments, as if it were a physics lab. We also included a photographic workshop and stores to provide all routine chemicals and supplies, thus avoiding delays in delivery. Finally, we appointed a service engineer to keep instruments in running order, rather than having to rely on firms to send us their own service men. These facilities were, and they still are unique, and they allow people to get on with their work faster than anywhere else I know.

Left: Max Perutz with his model of haemoglobin and John Kendrew with his model of myoglobin in 1962.

 


Making People Talk and Listen to Each Other

Experience had taught me that laboratories often fail because their scientists never talk to each other. To stimulate the exchange of ideas, we built a canteen where people can chat at morning coffee, lunch and tea. It was managed for over twenty years by my wife, Gisela, who saw to it that the food was good and that it was a place where people would make friends. Scientific instruments were to be shared, rather than being jealously guarded as people's private property; this saved money and also forced people to talk to each other. When funds ran short during the building of the lab, I suggested that money could be saved by leaving all doors without locks to symbolise the absence of secrets.


Left to right: Maurice Wilkins, John Steinbeck, John Kendrew, Max Perutz, Francis Crick and Jim Watson after the Nobel Ceremony in Stockholm in December 1962.


For most mortals, the Cavendish Professor of Physics used to be approachable only through his secretary's office. To do away with this barrier I ensured that the door of my office opened directly into the passage, so that anybody could just walk in. Once a foreign visitor did so unannounced and asked: "Can I give you a lecture?" When I replied: "No, thank you, not just now", he proceeded to give it, proudly demonstrating his diagrams on cards, instead of slides, to his captive audience.

Most laboratories hold seminars where its scientists report their work, but they are often attended only by those scientists' own group. To ensure that everyone is aware of all the work in the lab, Crick instigated an annual week of seminars which used to be known as Crick Week, to be attended by all members of the laboratory. He used to dominate it by his searching questions and sharp comments, and it was a sad day when he left us for the Salk Institute in La Jolla.

 

Enlightened Policies

The laboratory owes much of its success to the enlightened policies of the Medical Research Council, especially to Harold Himsworth, its secretary from 1949 to 1968, whose foresight and courage led him to support our early work for many lean years when we had little to show for it yet, and when there was only the faintest hope of it ever benefiting medicine.

Himsworth's staff did not burden us with bureaucratic rules and futile floods of paper, but saw it as their prime responsibility to help us carry out our research. I reported directly to Himsworth, rather than a Committee; he negotiated the annual grant to the Medical Research Council with the Treasury directly, rather than being allotted the Council's slice of the overall science budget by a ministerial committee, and he had the authority to take decisions within the broad lines of policy laid down by the Council. This system ensured smooth and efficient running, but Thatcherism has now destroyed much of it. Under her all-pervasive rule and in the name of "accountability", bureaucracy has multiplied and directors are burdened with mountains of paperwork that leaves them less time to devote themselves to scientific work, the talent for which (and not for filling in forms) earned them their positions in the first place.


Amazing Productivity

Fortunately, none of this has so far affected the amazing productivity of the Laboratory of Molecular Biology. Under Aaron Klug, its director since 1986, the laboratory has remained a magnet for talent from all corners of the world, and young as well as not so young scientists continue to solve problems that would have been considered beyond the reach of science only a short time ago. Some of these, such as Nigel Unwin's structure of the acetylcholine receptor, or Richard Henderson's atomic model of bacteriorhodopsin, or John Walker's mitochondrial ATPase structure, have required sustained efforts lasting many years and could never have been solved if we had had to depend on short-term grants. Best of all, some of our work is now finding applications in practical medicine, thus justifying Himsworth's early faith in molecular biology's future.



The Medical Research Council Laboratory of Molecular Biology when it was opened in 1962.


Photos: Courtesy of Prof. Max Perutz, The Medical Research Council Laboratory of Molecular Biology.

http://www.nobel.se/medicine/articles/perutz/index.html

History of Caltech

by Judith Goodstein
California Institute of Technology

 

The California Institute of Technology is a small, independent university of research and teaching in science and engineering, with 900 Ph.D.-level researchers, including almost 300 regular faculty, 900 undergraduates, and 1,000 graduate students. In spite of its small size, it has become one of the world's leading institutions of scientific research and education.

Caltech's beginnings are rooted in a modest little college founded in Pasadena in 1891 by wealthy former abolitionist and Chicago politician Amos Throop. Initially named Throop University, the school changed its name to Throop Polytechnic Institute in 1893. In its first fifteen years, Throop served the local community, teaching a great variety of subjects, from arts and crafts to zoology, with considerable emphasis on vocational training. By 1906, Throop needed a fresh sense of purpose. The American astronomer George Ellery Hale, the first director of the nearby Mount Wilson Observatory and a newcomer to Pasadena, would provide it.

Amos Throop
Courtesy of the Archives, California Institute of Technology

A scientist bubbling over with educational, architectural, and civic ideas, Hale was elected to the school's board of trustees in 1907 and promptly set about to transform it. He persuaded school officials to abandon Throop's high school and other programs and concentrate on expanding and developing the college along engineering lines; recruited James A. B. Scherer, who served as Throop's president between 1908 and 1920; and enticed Arthur A. Noyes, former president of MIT and the nation's leading physical chemist, to join him in Pasadena. In Noyes, Hale saw not only an opportunity to bring chemistry at Throop College (Throop officially changed its name to Throop College of Technology in 1913) up to a level with that at MIT but also to put Throop itself in the national limelight. The third member of Hale's scientific troika was the physicist Robert A. Millikan who began, in 1917, to spend several months a year at Throop as director of physical research.

Portrait of Noyes, Millikan and Hale hangs in the main dining room at the Athenaeum, Caltech.
Courtesy of the Archives, California Institute of Technology

The three of them spent the World War I years in Washington, organizing and recruiting scientists to work on military problems, but also building a superb network of contacts that would later serve the school well. Collectively ambitious for American science, eager to see their country play a larger role on the world's scientific stage, and determined to put Throop on the map, Hale, Millikan, and Noyes had become a formidable scientific triumvirate by 1918. By Armistice Day, they had set the stage to transform the engineering school into an institution that put pure science first.

Between 1919 and 1921, the school obtained a handsome endowment, drafted a new educational philosophy, took its present name, and selected a new man to guide its destiny for the next twenty-five years. Hale and Noyes wanted to use Caltech to reshape the education of scientists. Millikan wanted to make Caltech one of the physics capitals of the world. To do that, he needed research funds.The three men came to an agreement. Hale and Noyes promised Millikan the lion's share of the school's financial resources and minimal administrative duties as head of the Institute. In return, Millikan agreed to come, as director of the Norman Bridge Laboratory of Physics, and administrative head of the Institute. By then, Noyes had resigned from MIT and accepted a full-time appointment as director of chemical research in Pasadena.


In the early 1920s, Caltech was essentially an undergraduate and graduate school in the physical sciences. Indeed, until 1925, the institution offered graduate work leading to the doctorate only in physics, chemistry, and engineering. Geology joined the list of graduate studies in 1925, aeronautics in 1926; biology and mathematics in 1928. Physics was king from the very beginning. It had more students, more faculty, and more money than other departments had. Millikan initiated a visiting-scholars program shortly after his arrival in Pasadena. The list of scientists who accepted Millikan's invitation represented the cream of European physics, including Paul Dirac, Erwin Schrödinger, Werner Heisenberg, Hendrik Lorentz, and Niels Bohr. Albert Einstein's visits to the campus in 1931, 1932, and 1933 capped Millikan's plans to put physics on the map in southern California. If nothing else, Einstein's visits showed dramatically that the Caltech that Hale, Millikan, and Noyes had set out to build in the twenties had come of age in the thirties.

Millikan, who functioned as the school's president between the wars, was fiercely opposed to government funding of research. He relied on the major private foundations, especially the Rockefeller and the Carnegie, and a growing number of southern California philanthropists to provide the funds he needed. He believed that the modern world was basically a scientific invention, that science was the mainspring of the twentieth century, and that America's future rested on the promoting of basic science and its applications. Caltech, in Millikan's view, existed to provide America's scientific leadership.

Photo taken at March Field during JATO experiments with the Ercoupe airplane by USAF. Rockets developed by CIT/JPL. From left: C.B. Millikan, M. Summerfield, T. von Kármán, F.Malina and Capt. H.A. Boushey
Date: August 1941
Courtesy of the Archives, California Institute of Technology

The focus of scientific research at the Institute under Millikan during the 1930s ranged from Drosophila genetics and the biochemistry of vitamins in biology, to the theory of turbulence and airplane wing design in aeronautics; from cancer therapy with radiation and the radioactivity of the light elements in nuclear physics, to soil erosion and the transmission of water from the Colorado River to Los Angeles in engineering; from the application of quantum mechanics to molecular structure in chemistry, to the introduction of the magnitude scale in seismology.

An educational institution in name only during the war, Caltech had a war arsenal that included rockets, proximity fuses, the Jet Propulsion Laboratory, and $80 million in federal funds for war-related research and development.

Caltech's history is divided into two distinct eras. The first Caltech era was created by Hale, Millikan, and Noyes. Thirty years later, after World War II, the physicists Lee Alvin DuBridge and Robert Bacher did the job all over again. DuBridge, the head of MIT's wartime radar project, became Caltech's new president in 1946. Bacher, the leader of the Los Alamos atomic bomb project's "G" Division (the "G" stood for gadgets), arrived in 1949 to head up the division of physics, mathematics, and astronomy and later became the Institute's first provost.

During DuBridge's tenure (1946-1969), Caltech's teaching faculty doubled in number, the campus tripled in size, and new research fields blossomed, including chemical biology, planetary science, nuclear astrophysics, and geochemistry. 1948 saw the dedication of a new 200-inch telescope on Palomar Mountain, the world's most powerful optical telescope for more than forty years. Unlike Millikan, DuBridge argued that the federal government had a responsibility to support scientific research.

Robert Bacher and Lee Alvin DuBridge
Courtesy of the Archives, California Institute of Technology

As Caltech's new physics head, Bacher rebuilt the physics department, and he did so with a vengeance, starting with high-energy particle physics. Then a new field, particle physics hardly existed at Caltech in 1949, except for the work of Carl Anderson and his students, including Donald Glaser, a later Nobel-Prize winner, who used cosmic rays from space as a natural source of high-energy particles to do particle physics. While chairman, Bacher initiated construction and use of a new electron accelerator, so that the Caltech group could make its own high-energy particles. The Institute closed down its electron synchrotron in 1969, shortly after ground was broken for the national accelerator laboratory--Fermilab, in Batavia, Illinois. Theoretical physics, always a stepchild under Millikan, entered a golden age with the acquisition of Richard Feynman and Murray Gell-Mann. Feynman, then at Cornell, was Bacher's first acquisition.

Richard Feynman lecturing.
Courtesy of the Archives, California Insitute of Technology.

Historical studies of the development of Caltech as a research university after the war are scarce. There are no biographies of key figures from George Beadle, Charles Richter, and William Fowler onwards.

 


 

Bibliography

Ajzenberg-Selove, Fay. "A Matter of Choices: Memoirs of a Female Physicist." New Brunswick: Rutgers University Press, 1994.

Florence, Ronald. "The Perfect Machine: Building the Palomar Telescope." New York: HarperCollins, 1994.

Geiger, Roger L. "Research and Relevant Knowledge: American Research Universities since World War II." New York: Oxford University Press, 1993.

Goodstein, Judith R. "Millikan's School: A History of the California Institute of Technology." New York: Norton, 1991.

Gorn, Michael H. "The Universal Man: Theodore von Karman's Life in Aeronautics." Washington, D.C.: Smithsonian Institution Press, 1992.

Kargon, Robert. "The Rise of Robert Millikan: Portrait of a Life in American Science." Ithaca: Cornell University Press, 1982.

Kevles, Daniel J. "The Physicists: The History of a Scientific Community in Modern America (1978)." Paperback reprint, with a new preface, Cambridge, Mass.: Harvard University Press, 1995.

Murray, Bruce C. "Journey into Space: The First Three Decades of Space Exploration." New York: Norton, 1989.

Reingold, Nathan. "Science and Government in the United States since 1945." History of Science 32 (1994):361-386.

Servos, John W. "Physical Chemistry from Ostwald to Pauling: The Making of a Science in America." Princeton: Princeton University Press, 1990.

Sinsheimer, Robert. "The Strands of a Life: The Science of DNA and the Art of Education." Berkeley: University of Calfornia Press, 1994.

http://www.nobel.se/medicine/articles/goodstein/index.html

Emil von Behring: The Founder of Serum Therapy

Based on an exhibition at Marburg Castle*
Arranged and documented by Kornelia Grundmann

 

Upbringing and Education

Emil Behring (1854-1917) was born on March 15, 1854 in Hansdorf, West Prussia, as the first child of the couple August and Auguste Behring. His father was a village school teacher, who during his first marriage had had four children and after the birth of Emil had another eight children.

A talented pupil, Emil Behring was above all assisted by the village minister, who made it possible for him to attend the Gymnasium (High School) in the village Hohenstein. His orientation as a theology student appeared to have changed after a friend who was a military doctor arranged for him to start his medical studies at the University of Berlin. He obtained a scholarship and from 1874 through 1878 he studied at the Academy for Military Doctors at the Royal Medical-Surgical Friedrich-Wilhelm-Institute, where he also earned his medical degree. In the following years he had to perform as a military doctor and also worked as a troop doctor in various garrisons. After having been assigned as captain of the medical corps to the Pharmacological Institute at the University of Bonn, he was given a position at the Hygiene Institute of Berlin in 1888 as an assistant to Robert Koch (1843-1910), one of the pioneers of bacteriology. During this time, Behring's first authoritative publication on diphtheria and tetanus serum therapy appeared.

Emil von Behring in a military uniform.
Photo: Courtesy of Aventis Behring

 

The Behring Family

During his early years as a military doctor, Behring's income was not sufficient for him to think about starting a family. Only in 1896, when he had a regular salary, did he marry the 20 year old Else Spinola. They went on a three-month honeymoon to the island of Capri. Else, born August 30, 1876 in Berlin, was the daughter of Werner Spinola, Administrative Director of Charité, the university medical clinic in Berlin.

In 1898, after having become professor at the University in Marburg (then part of Prussia), Behring moved with his family into a house in Wilhelm-Roser-Strasse in Marburg, where his six sons were born. Behring was a family man, though rather patriarchal, which at that time was quite normal. In the circle of his family he felt content, although his scientific work presumably did not leave him much time for his wife and children.

Wedding picture of Emil and Else von Behring.
Photo: Courtesy of Aventis Behring

On March 31, 1917, Behring died and was entombed in a mausoleum at the Marburg Elsenhöhe. After Behring's death, Else von Behring served as chairwoman of the Women's National Organisation in Marburg, Germany. She died in 1936 of a heart attack at the age of only 59.

 

Family and Friends

On the list of his sons' godfathers, it appears obvious who stood closest to Emil von Behring besides his family. His first son, Fritz, had the bacteriologist Friedrich Loeffler (1852-1915) and Behring's friend and co-worker, Erich Wernicke as godfathers. The godfather of his third son, Hans, was the Prussian Under-Secretary of Education and Cultural Affairs, Friedrich Althoff. His fifth son, Emil, had as a godfather the Russian researcher Elias Metschnikoff (1845-1916), founder of the theory of phagocytosis, with whom Behring had continuous scientific exchange of ideas. Emil's second godfather was the pupil of Louis Pasteur, Émile Roux (1853-1933), who like Behring Sr. dealt with the fight against diphtheria. In 1913, the godfather of his sixth son, Otto, was the physician Ludolph Brauer (1865-1951), who had taught together with Behring at the Marburg Medical Faculty as a professor of internal medicine.

 

The Development of the Diphtheria-Therapeutic-Serum

Behring, who in the early 1890s became an assistant at the Institute for Infectious Diseases, headed by Robert Koch, started his studies with experiments on the development of a therapeutic serum. In 1890, together with his university friend Erich Wernicke, he had managed to develop the first effective therapeutic serum against diphtheria. At the same time, together with Shibasaburo Kitasato he developed an effective therapeutic serum against tetanus.

Behring together with his colleagues Wernicke (left) and Frosch (center) in Robert Koch's laboratory in Berlin.
Photo: Courtesy of Aventis Behring

The researchers immunized rats, guinea pigs and rabbits with attenuated forms of the infectious agents causing diphtheria and alternatively, tetanus. The sera produced by these animals were injected into non-immunized animals that were previously infected with the fully virulent bacteria. The ill animals could be cured through the administration of the serum. With the blood serum therapy, Behring and Kitasato firstly used the passive immunization method in the fight against infectious diseases. The particularly poisonous substances from bacteria – or toxins - could be rendered harmless by the serum of animals immunized with attenuated forms of the infectious agent through antidotes or antitoxins.

Shibasaburo Kitasato.
Photo: Courtesy of Aventis Behring

 

The Introduction of Serum Therapy

The first successful therapeutic serum treatment of a child suffering from diphtheria occurred in 1891. Until then more than 50,000 children in Germany died yearly of diphtheria. During the first few years, there was no successful breakthrough for this form of therapy, as the antitoxins were not sufficiently concentrated. Not until the development of enrichment by the bacteriologist Paul Ehrlich (1854-1915) along with a precise quantification and standardization protocol, was an exact determination of quality of the antitoxins presented and successfully developed. Behring subsequently decided to draw up a contract with Ehrlich as the foundation of their future collaboration. They organized a laboratory under a railroad circle (Stadtbahnbogen) in Berlin, where they could then obtain the serum in large amounts by using large animals – first sheep and later horses.

In 1892, Behring and the Hoechst chemical and pharmaceutical company at Frankfurt/Main, started working together, as they recognized the therapeutic potential of the diphtheria antitoxin. From 1894, the production and marketing of the therapeutic serum began at Hoechst. Besides many positive reactions, there was also noticeable criticism. Resistance, however, was soon put aside, due to the success of the therapy.

 

The Marburg Years

Behring was given the opportunity to start a university career through one of the leading officers (Ministerialrat) of the Prussian Ministry of Education and Cultural Affairs, Friedrich Althoff (1839-1908), who wanted to improve the control of epidemics in Prussia by supporting bacteriological research. After a short period as professor at the University of Halle-Wittenberg, Behring was recruited by Althoff to take over the vacant chair in hygiene at Philipps Marburg University on April 1, 1895. His appointment as full professor followed shortly thereafter against the will of the faculty, who besides all of Behring's outstanding discoveries, wanted a university lecturer who would broadly represent the field. However, Althoff rejected all counterproposals and Behring took over as Director of the Institute of Hygiene at Marburg. His position included giving lectures for hygiene and concurrently held a teaching contract in the history of medicine. In 1896, the Marburg Institute of Hygiene moved to a building on a road nearby Pilgrimstein Road, previously the Surgery Clinic. Behring divided the Institute into two departments, a Research Department for Experimental Therapy and a Teaching Department for Hygiene and Bacteriology. He remained Director of the Institute until his retirement as professor in May 1916.

 

Scientific Contacts

Behring belonged to a scientific discussion group called "The Marburg Circle" (das Marburger Kränzchen), whose other members were the zoologist Eugen Korschelt (1858-1946), the surgeon Paul Friedrich (1864-1916), the botanist Arthur Meyer (1850-1922), the physiologist Friedrich Schenk (1862-1916), the pathologist Carl August Beneke (1861-1945) and the pharmacologist August Gürber (1864-1937). They often met at Behring's home where they had rounds of vivid and prolific scientific discussions.

 

Active Protective Vaccination against Diphtheria

Old vials (1897 and 1906) with hand-written labels.
Photo: Courtesy of Aventis Behring

The therapeutic serum developed by Behring prevented diphtheria for only a short period of time. In 1901, Behring, therefore, for the first time, used a diphtheria innoculation of bacteria with reduced virulence. With this active immunization he hoped to help the body also produce antitoxins. As a supporter of the humoral theory of immune response, Behring believed in the long-term protective action of these antitoxins found in serum. It is well-established knowledge today that active vaccination stimulates the antitoxin (antibody) producing cells to full function.

The development of an active vaccine took a few years. In 1913, Behring went public with his diphtheria protective agent, T.A. (Toxin-Antitoxin). It contained a mixture of diphtheria toxin and therapeutic serum antitoxin. The toxin was meant to cause a light general response of the body, but not to harm the person who is vaccinated. In addition, it was designed to provide long-term protection. The new drug was tested at various clinics and was proven to be non-harmful and effective.

 

Tetanus Therapeutic Serum during World War I

In 1891, tetanus serum was introduced considerably more quickly in clinical practices than the diphtheria serum. The Agricultural Ministry supported research efforts to develop a therapeutic agent against tetanus to protect agriculturally valuable animals. The large amounts of serum required were obtained through the immunization of horses. However, there was no substantial clinical testing on humans; this led the Military Administration to accept it only on a small scale at the beginning of World War I.

During the first months of the war, this restraint led to massive losses of human lives. Also, after the distribution of the tetanus antitoxins in the military hospitals, many futile attempts at therapy were noted. At the end of 1914, as a result of Behring's constructive assistance, the injection of serum was established as preventing disease. Starting in April 1915, the mistakes in dosage and the shortage of supplies were overcome and the numbers of sick fell dramatically. Behring was declared "Saviour of the German Soldiers" and was awarded the the Prussian Iron Cross medal.

Historical engraving showing how the medicinal serum was obtained from immunized horses.
Photo: Courtesy of Aventis Behring

 

An Attempt to Develop a Therapeutic Method against Tuberculosis

After Robert Koch had failed with his tuberculosis therapy in 1893, Behring began to search for an effective therapeutic agent against this disease. However, very soon, he had to admit that combating tuberculosis using a healing serum was not feasible. Therefore, he concentrated on working on a preventive vaccination, which, however, required precise knowledge of the mechanism of infection. In Behring's view, the tubercle bacillus was transmitted to children through the milk of a mother or a cow infected with tuberculosis. He then started treating milk with formaldehyde, so as to eliminate this source of infection. This procedure was not accepted due to the bad smell of the milk. Moreover, the transmission of tubercle bacilli through the respiratory tract was proven to be more likely than through the digestive system, as had been claimed by Behring.

From 1903, Behring worked on active immunization through attenuated tuberculosis infectious agents, which he then tried on cows, however, with only moderate success. His aim was to obtain a protective and therapeutic agent for humans. A number of agents (tuberculase, tulase, tulaseactin, tulon) failed to make a breakthrough. At the beginning of World War I, Behring halted his efforts to combat tuberculosis and dedicated himself entirely to the further development of tetanus serum.

 

Behring's Relationship to Paul Ehrlich

Paul Ehrlich was Behring's colleague at Robert Koch's institute. Here, he was able to work out a reliable and reproducible standardization method for diphtheria serum. However, in later years, tension developed between the two researchers. Differences with Ehrlich's pupil, Hans Aronson, resulted in bad feelings, which increased when Ehrlich's Royal Institute of Experimental Therapy was founded at Frankfurt/Main. The previous friendship between the two researchers never fully succumbed, through the mediation of Friedrich Althoff. However, it was subsequently demonstrated that the only photograph showing Behring and Ehrlich together, which appeared on the cover of a Berlin newspaper on the occasion of their 60th birthday in 1914, was a photomontage made up of two separate photographs.

Report of the Berliner Illustrirte Zeitung (Berlin Illustrated Newspaper) about Emil von Behring and Paul Erlich and their work on the occasion of their 60th birthday.
Photo: Courtesy of Aventis Behring

 

Behring's Health

Behring lived entirely for his idea of revolutionizing medicine through serum therapy. This idea hung above him and motivated him, in his own words, "like a demon." His enormous concentration on his work often drove him to physical illnesses, as well as to deep depressions, which forced him to take time off work for a sanatorium stay from 1907 through 1910.

 

Acknowledgements and Honors

In 1903, Emil von Behring was given the title of "Wirklicher Geheimer Rat mit dem Prädikat Excellenz" by the German emperor Wilhelm II. The diploma says: "This is in order that Behring should remain in unbroken loyalty to Myself and the Royal Family and to fulfill his official responsibility with continuous eagerness, whereby he who has the right connected to his present character, will receive the highest protection by Myself". A splendid uniform was provided along with the title.

In 1901, when the Nobel Prizes were awarded for the first time, Behring received the Prize in Physiology or Medicine.

A detail (right) and the diploma for the first Nobel Prize in Physiology or Medicine, awarded to Behring in 1901.
Photo: Courtesy of Aventis Behring

 

Behring Jubilee in 1940

On December 4, 1940, the Philipps University Marburg celebrated the 50th anniversary of the original publication of Emil von Behring's decisive discovery of serum therapy. Top leaders of the National Socialist Party, the rectors of numerous German universities, representatives of the Behringwerke and many scientists and friends of Emil von Behring from abroad were also present. The celebration, which continued over a few days, began with lectures and addresses by officials, both of the state and party. Finally, a foundation certificate for a new Institute for Experimental Therapy was handed over. The professors then moved from the university auditorium (Aula), to unveal a new Behring Memorial close to the St. Elisabeth Church. The celebration was followed by a two-day scientific meeting, presenting the state of the art of immunology and the fight against infectious diseases.

 

The Background of the Celebration

In the view of the National Socialists, Else von Behring was regarded as a "half-Jew", as her mother came from a Jewish family. With the help of a number of friends she was able to get her sons accepted by Hitler as "Aryans" and not stigmatized as "half-breeds". After the death of Else von Behring in 1936, no obstacles were left for the Nazi party to use Emil von Behring as a glorified representative of national socialist "Germanic" science. During the ceremony there were, however, some signs of tension. Although one of Behring's sons participated in the ceremony, he was not greeted by any of the official speakers. Only the Danish researcher, Thorvald Madsen from Copenhagen, who had previously been chairman of the Health Organisation of the League of Nations, dared to mention Behring's friendly connection with researchers from enemy countries, such as those at the Institute Pasteur in Paris. Courageously, he also recalled the great bacteriologist Paul Ehrlich, despised by the Nazis due to his Jewish origin, who had played a significant role in Behring's successes.



*The exhibition is from October to December 2001.

Translated by Gabriella Nichols, Department of Anatomy, Philipps University Marburg, Germany.

 

   

Published with the support of

http://www.nobel.se/medicine/articles/behring/index.html