Interview with Dr. Richard Krause

Harden: Dr. Krause, would you summarize your career before 1981, when AIDS was identified, and perhaps indicate your areas of special interest and research? How do you think these might have helped prepare you for encountering this disease?

Krause: After medical school I was trained in internal medicine at Barnes Hospital in St. Louis. Before that, during medical school, I took eighteen months off and worked with the late Dr. Charles H. Rammelkamp of Case Western Reserve University School of Medicine. He was working on the prevention of rheumatic fever by early treatment of streptococcal sore throat with penicillin. There was an argument at the time as to whether treatment would prevent subsequent rheumatic fever. This was between 1948 and 1950. “Rammel,” as we called him, was convinced that rheumatic fever could be prevented, but most people at that time disagreed with him. A long series of clinical and epidemiological studies by Rammel and his group proved without question that this could be done. They received the Lasker Group Award for this work.

It was great fun to be associated with Rammel and this clinical epidemiological research, in which the laboratory, the clinic, and the fieldwork were all a unit. Some believed then, and some do even today, that epidemiology should be pure and not be contaminated with laboratory work or clinical work. I think this early experience really prepared me for the position of director of NIAID and for the AIDS epidemic.

Also, for a period of about four months during World War II, I worked in a venereal disease control program in the U.S. Army. I was an enlisted man at the time with no medical training. I remember very well the sexually transmitted diseases (STDs) control programs and the measures that were taken. Many of these have been advocated in the 1980s for the prevention of the transmission of AIDS and STDs.

After graduation from medical school and two years of training in internal medicine at Barnes Hospital, I went to Rockefeller University from 1954 to 1975. There I did clinical investigation on patients with rheumatic fever, but most of my research was concerned with immune response to streptoccocal antigens. I made the discovery in the early sixties that immunized rabbits produced antibodies of remarkable molecular uniformity and in large quantities. This was before monoclonal antibodies had been prepared by Dr. Cesar Milstein and Dr. Georges Köhler. Therefore, from 1965 until 1976, our work was a very useful source of homogeneous antibodies, either for structural studies on antibodies or as probes for research in immunogenetics. A great deal was done on the genetics of the immune response using these antibodies particularly by my former associates, Dr. Thomas Kindt, the laboratory chief at NIAID, Dr. Klaus Eichmann, Director of the Max Planck Institute of Immunology, Freiburg, and Dr. Dietnam Braun, CibaGeigy, Basel.

I came into the directorship of NIAID therefore, with a broad background in microbiology and immunology, and with an interest in clinical medicine and clinical epidemiology. Because of my background, when I was appointed director, the microbiologists thought that I was a microbiologist and the immunologists thought that I was an immunologist. Both groups were disappointed, because after a year or two, I supported both camps and not one or the other. There is nothing you can do about that.

One of the first things that happened after I joined the government was the “swine flu affair,” which occurred during the winter of 1975-76. Several young men died at Fort Dix of a strain of swine flu virus thought to be related to the virus that caused the pandemic of 1918. There were approximately five hundred young men who were infected, but this was a mild infection, except for the one or two deaths.

There is no point in reviewing that whole history in detail. On the basis of a few cases, we put on a major effort to develop the swine flu vaccine and prepared to immunize the population. The experts all agreed that it was the only thing to do, and I think that most would make the same decision today, given the same set of facts. The pandemic of World War I hung over our decision. We knew that vaccination was the only way to get ahead of an epidemic, since influenza often begins in one season and then bursts into the next. So we went ahead, made vaccine, and immunized forty million people. Influenza did not occur the following season. After that we had a change of administrations.

Mr. Joseph Califano came in as the Secretary of HHS [Department of Health and Human Services]. There was a good deal of second guessing about the swine flu effort. It is not clear to me how I could have played a different role one way or the other. But that left an impression on me–committing major resources to a potential problem, which afflicted only a few. The cause of these people's deaths was an unexpected strain of flu. As a result, there was an incredible mobilization, and this led to serious repercussions.

Would I, along with the others have made a different decision? Probably not. But in retrospect, maybe rather than use it, we should have stockpiled the vaccine until we were certain about the possibility of an epidemic. However, experts like Dr. Albert Sabin said at that time, about February or March of 1976, that if we did not immunize the children before they went to school in September, we would not stop the epidemic. This is because flu spreads after the children are brought together, and once it starts spreading in the schools, it is transmitted to the families. I remember that from the meeting in the White House cabinet room with President Gerald Ford. The consensus of the group was to vaccinate early, not just to stockpile the vaccine.

Another episode sensitized me to the political reaction to commitment of resources to the treatment of less common illnesses. An NIAID achievement, when I came on board, was the use of pure bee and wasp venom for desensitizing patients who were at risk of fatal anaphylaxis after a sting. This was a major advance, because before that time, desensitization was not very successful. [Dr.Lawrence M.] Lichtenstein at Johns Hopkins [University] developed a desensitization method using pure venom. It worked beautifully. Sensitive people can die from bee or wasp stings, particularly people who work outdoors, surveyors, engineers, telephone linemen...farmers. Once you have successfully desensitized the person who is in danger of fatal anaphylaxis, no reaction occurs when such people are deliberately stung by a wasp in the clinical laboratory. So that was very impressive.

The point is this. When we go before the appropriations committees of Congress, we must describe achievements of the previous year. Senator [Thomas] Eagleton was in the chair and asked about new advances, or something to that effect; you can find it in the record. (The records of congressional testimony would be a useful place to find what Dr. Vincent De Vita and I said about AIDS in the 1980s.) So I explained what we had done about bee stings. I could see that Senator Eagleton was not impressed. I could see it in his face. He asked, “Dr. Krause, how many people die each year of bee and wasp stings?” I said perhaps fifty, perhaps 100. He replied that that was of course unfortunate, but I could see he did not consider this a major health issue. For all I know it could be 500 or 1,000 people. Certainly it is not a large number. On the other hand, there are many, many thousands of people who live in fear of death, because they know what a severe reaction they can have, and they are appreciative of this medical advance.

Nevertheless, that episode sensitized me to being evenhanded in the use of scarce resources for a smaller number of patients. Of course, they are important. But there were many problems, many demands from 1975 to 1985, and the NIAID was stretched very, very thin. For years it had the lowest pay line (the percentage of approved grants paid) of all the institutes. Too many scientists thought infections were no longer important and that view was translated into a decision in NIAID's budget.

When I took over as Director of NIAID, Dr. Lewis Thomas said, and even Dr. Don [Donald] Fredrickson said, “Now that we've conquered infectious diseases, and we don't have to worry about them any longer, we'll worry about heart disease and cancer and so forth.” Lew Thomas has since taken that back. I wrote him a letter saying, “I'm delighted you've rejoined the Mother Church, it has been very lonely here on the front line with everybody having deserted us.” He wrote a charming note, “I never left the Mother Church. I was over in a quiet corner praying before the candles for the diseases we do not know about, such as kuru.”

That was the picture when AIDS occurred. NIAID was spread very thin, a little bit like the Confederate forces during the Civil War, and we had to be selective in what we did. We could not put our fingers in every leak in the dyke. As important as small numbers of patients are, with limited resources, we had to be selective. When push came to shove, rightly or wrongly, I usually made the decisions for broad-based biomedical research, because the fundamental answers to immunological diseases and virus infections were going to take a lot more research to understand; for example, how to treat immunologic and virus diseases and how to prevent them. There is no penicillin for virus infections. So, in general, when push came to shove, I was on the side of substantial support for basic research and as much applied research as we could afford. And we could not afford as much as NCI [National Cancer Institute] or NHLBI [National Heart, Lung and Blood Institute] could.

And yet, if we were to receive an increase in the budget resources from the administration and Congress, we had to make a case for it in the disease arena. It is very hard to sell basic research alone.

So in the 1970s, from 1975 to 1980, I organized a series of task forces on virus infections, on immunologic diseases, on sexually transmitted diseases, and on asthma and allergic diseases. A lot of work was done by the extramural and the intramural scientists to produce the reports of these task forces. They produced guiding principles for the priorities of the institute on what was needed in basic research and clinical research. This was all done just before the AIDS epidemic struck. Between 1975 and 1980, the NIAID budget increased by 100 percent. So we were beginning to have an impact.

During that time, the staffers on the Hill were pushing us to do something, to get the word out to the public, about herpes, etc., and so we did. We brought out a very good movie called Jennifer: The Revealing Story of Genital Herpes. You may want to see it sometime. It is a very good movie, and it was very well done. So we were very much involved in the STD business, and I pushed this. It was one of our special programs. It was something that I knew was a serious problem because of my days in World War II. I was sensitized to it. During wartime you have societal changes, resulting in the same sort of thing as the sexual revolution of the sixties and seventies, but for different reasons. Certainly during wartime you have a change in mores.

Harden: I would like to come back to that later, about comparing other STDs and AIDS.

Krause: Right. To inform the public I wrote a book on the fact that infections were not going to go away. It only takes twenty-four hours for an epoch to come and go in the microbial world. Microbes reproduce every thirty minutes. We reproduce every twenty years; therefore, a season to us is a millennium for them. They can come and go in a season. We do not come and go that fast. That means that they have a tremendous genetic advantage over us, and always will have. They were here, on earth, for two billion years before we arrived, and they are going to be here for probably two billion years after we are gone. In any event, this ebb and flow of microbes and humans I put into a book titled The Restless Tide. I do not know whether you have seen it. Margaret McElwain, the information officer at NIAID, worked on this with me. I dedicated the book to her. She died in 1978, which put me back a bit, but then I finished it with Nancy Brun's help. It was all ready to go to press in 1980, when we had some arguments with various publishers, and nothing was done until March 1982, when it finally came out. By that time there had already been the first AIDS report in 1981.

I did not mention AIDS in the book, but the book was reviewed in the national gay newspaper, the Advocate. I think it was Nathan Fain who did the health reporting in the Advocate. I did read the Advocate from time to time to read his health articles, particularly since he was writing in the Advocate about AIDS. He was one of the early people who talked about behavior modification. In his review, he referred to me as the man who predicted the AIDS epidemic. I did not predict AIDS, but I did predict we would not see an end of infection as the cause of human misery. That pretty much brings this history up to where I was prepared to worry about AIDS.

Harden: All right. Let us look back and think in terms of diseases striking the human population, for example, when syphilis hit in the early sixteenth century. In Europe, it was a very deadly disease, and something that could not be dealt with easily, like another disease–the bubonic plague. When a disease that we do not understand strikes a society, it can cause great panic. Do you think more panic might have resulted from AIDS if it had hit us in 1955, before we knew about B cells, T cells, and retrovirology?

Krause: There is no doubt, as others have commented, that if AIDS had to strike, we were prepared because of the research advances between 1950 and 1981. We are a long way from a vaccine, although I hesitate to make a prediction like that, because something may come out of the woodwork in another year or so. Finding a drug to treat any virus infection has been tough, but it is not impossible. It has been done before. We have amantadine and rimantadine to treat flu. And, acyclovir is effective in the treatment of herpes. It does not cure the latent infection, but it has made a big difference in the treatment of the herpetic lesions. There are a few other antiviral drugs, but not many. Developing antivirals is not like developing antibiotics for bacteria. It is tougher, due to the nature of the virus infection process that is so intimately associated with cellular mechanisms of the human host. Transcripts