Virus Safety of Hemophilia Treatment in Germany and Austria-a Review of the Past 15 Years: A Eulogy for the 70th birthday of Professor Dr. rer. nat. Norbert Heimburger

It is now more than a quarter of a century since Professor Heimburger and I first met. It was in 1971 in Marburg at the Annual Conference of the Deutsche Arbeitsgemeinschaft für Blutgerinnungsforschung (DAB). The DAB was a well-defined forum for meetings between basic scientists and clinicians, and you can imagine what lively discussions took place when biochemists presented their views to physicians. To a physician, a hemorrhagic diathesis is a condition in which bleeding occurs, whereas biochemists analyze this process and group the processes in patterns that change from year to year. I cannot remember what factor was at issue then in Marburg, but in any case it was very confusing. You, Professor Heimburger, tried to simplify the entire thing during the discussion by breaking the process up into manageable complexes, but you were rudely interrupted by a colleague: ``It's not that simple, Professor Heimburger. That's how any Tom, Dick, or Harry imagines clotting to be.'' The answer was not long in coming; it was calm, relaxed, and humorous (Fig. [1]): ``Firstly, I'm not just any Tom, Dick, or Harry, and secondly, what is so wrong about ordinary people trying to make it simple?''

This answer reflects two typical characteristics: you argue with facts; after all, you are Norbert and not any Tom, Dick or Harry, and secondly you have a gift for explaining complex things simply but accurately.

This makes you an important link with the clinical world, a fact that is particularly appreciated by us pediatricians. At that time in Marburg, every baby was thought to be at risk of hemorrhage, because the basic scientists wanted us to believe that babies had an immature clotting system because of their low levels of coagulation factors. You, Professor Heimburger, with your vision of clotting inhibitors, showed us even then that babies must have a compensation mechanism. This was long before anything was known about antithrombin or protein C or S. Today, we know that these factors are also reduced in babies. That is why basic scientists have recently started regarding babies as ``thrombophilic.'' Fortunately, babies are oblivious to these laboratory parameters, and your investigations have shown that they have an optimal clotting system, although it differs from that of adults. Newborn infants are after all not little adults.

Another main area of your research, fibrinolysis, has not only benefited countless adults with myocardial infarction, but also helped us pediatricians to use streptokinase successfully in infants. Your views on the proactivator-plasminogen complex helped explain the paradox that if a hemorrhage occurs during streptokinase therapy, the dose of streptokinase must be increased and not reduced, as unfortunately used to happen so often. You then invited me to Marburg and gave me vital assistance in developing a capillary blood test that allows the proactivator-plasminogen complex to be determined within a short time from just one drop of blood. The graphic of the test result also looks very pretty; our medical technicians called it Heimburger's onion (Fig. [2]).

However, your greatest contribution to pediatrics, Professor Heimburger, is the development of virus-safe coagulation factor concentrates.

We in Münster had the good fortune to be able to use the concentrates as early as 1979. All hemophilia patients at that time were extremely concerned about the risk of hepatitis infection through factor VIII products, so we were highly motivated to look for alternatives. In Münster, we were testing plasma-free desmopressin (DDAVP, or Minirin). The results were excellent in von Willebrand's disease and in mild and even moderate hemophilia, but sadly DDAVP did not work in severe hemophilia, and so the search for a hepatitis-safe treatment went on. It was my doctoral student of the time, Mr. Pollmann, who drew my attention to a new hepatitis-safe (HS) sterilization process, and when I heard the name Heimburger I was no longer in any doubt that this was the right one. However, we were lucky in several ways: first because we used very little factor VIII, so we were able to get hold of enough of the new concentrate, which initially was in short supply. Another piece of luck was that Professor Schellong, as Hospital Director, gave us the freedom of action that we needed. One additional unexpected piece of good fortune was that your HS substance was safe not only from the hepatitis virus but also from the AIDS virus, which was not discovered until several years later. In this way, Professor Heimburger, you saved many young patients from being infected with the AIDS virus. That is indeed your greatest achievement in pediatrics. Many pediatricians also contributed to the report in the renowned New England Journal of Medicine (Fig. [3]).

Finally, Professor Heimburger, I would like to look at your curriculum vitae for the key to your success.

You were born on February 16, 1926, in Rohr near Rummelsburg in Pomerania. This means that you come from the East, from the Baltic region, like so many other pioneers of coagulation research: Alexander Schmidt was from Dorpat, Virchow from Schivelbein, Morawitz from St. Petersburg, Erik von Willebrand from Helsinki, and Billroth from the island of Rügen. No wonder your place of birth marked you out as a specialist in hemostasis. Prof. Rudolf Marx, who was later our esteemed DAB president and would undoubtedly have delivered this eulogy in Latin, would have said at this juncture: ``Ex oriente lux haemostaseologica (From the east comes the light of hemostaseology).

At the beginning, however, you were hiding your light under a bushel. You are one of several major figures about whom a primary school teacher said: ``Nothing will come of him.'' At that time, you were a member of a Pomeranian gang of four (Fig. [4]) whose evil deeds I have heard about but will not speak of, just in case they are not all covered by the statute of limitations. I would, however, like to quash the rumor that the Cockchafer Song containing the words ``Pomerania is all burnt down'' appeared soon after this photograph was taken. Perhaps, though, the fire in the stand at the Rohr sports ground, which has not been explained to this day, provided you with the first clues about the thermal denaturation of fibrinogen.

Professor Heimburger, you showed at an early age the love of fast cars that you have had ever since. In this picture (Fig. [5]), we also see another of your characteristics-far-sightedness-because the license plate contains the initials of your wife Ingrid, whom you married in 1956.

In the next picture (Fig. [6]), you can see his predilection for sailor suits, which he was still wearing at the age of 15 in 1942 when he was deployed as a navy auxiliary. In 1943, at the age of 17, he joined the army. The following is a quote from his CV: ``I was taken captive by the Americans and handed over to France. Faced with the choice of going to Indochina as a legionnaire or clearing mines in France, I chose the latter.'' After he had cleared 1000 mines, he was released from captivity in the autumn of 1947.

I think that that was a valuable skill to learn for an academic career-the ability to deal with mine fields. First, however, came university study in Freiburg as a ``work student,'' as it was known then (Fig. [7]), culminating in the conferment of a doctorate (Dr. rer. nat.) in 1954. The subject of your thesis on behavioral physiology, ``Analysis of learning processes in mice in a 3-dimensional maze,'' was given to you by zoologist Prof. Otto Köhler. The results were undoubtedly useful later when coming to grips with the clotting cascade.

A research grant from the German Research Foundation (DFG) in 1956 allowed you to benefit from tuition by Professors Staudinger, Butenandt, and Turba.

Here's another quotation from your CV: ``In 1958 when Prof. Turba was appointed to the Chair of Physiological Chemistry in Würzburg he wanted to take me with him, but could not get a post for me. . . . So to fill in, I worked at the State Dairy Training and Research Institute at Wangen in the Allgäu.'' This is a well-known center of the cheese-making industry. Whereas the other workers at the Institute were concerned with how milk curdles, you were more interested in how milk does not curdle. This did not do much for your career in the cheese-making industry. However, you took this experience with you when you moved from Wangen to the Behringwerke in Marburg and made the small step from milk curdling to blood clotting (Fig. [8]). There, you were also working on clotting inhibitors, a new type of factors that no one understood at all then. I am told that your studies of inhibitors inhibited your own advancement in the Behringwerke for more than a decade. However, when the importance of the antithrombin concentrate developed by you was recognized many years later, doctors had a means of effectively controlling the process of excessive blood clotting. This recognition was followed by an increase in the size of your workforce, which became an extremely successful team (Fig. [9]).

Professor Heimburger, in 1991 you were honored by President Weizsäcker with the Order of Merit of the Federal Republic of Germany on a ribbon for your pioneering work in the field of hemostaseology (Fig. [10]). We pediatricians can merely thank you on behalf of the children your research has helped so much.

As a small token of recognition, we present a CD of the German Pediatrician's Orchestra in Würzburg playing works by Richard Strauss and Mozart.

The place and the music are important. We all love the beautiful city of Würzburg, but with hindsight we are of course glad that you did not get the position there and that, after the brief diversion via milk curdling, you ended up working on blood clotting. Richard Strauss, whose Horn Concerto can be heard on the CD, is a fellow countryman of your wife, with whom you will be celebrating your 40th wedding anniversary this year.

You, in collaboration with Professor Mingers in Würzburg, also were the first to describe homozygous type I plasminogen deficiency. As a small birthday present, I can inform you that this pioneering article will be published by the highly regarded American journal Seminars in Thrombosis and Hemostasis. At any event, this shows that you are still very active, despite having retired. We are very pleased that you will be able to go on telling us how Tom, Dick, or Harry should imagine blood clotting to be (Fig. [11]).