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Harden: Was the FACS machine (fluorescent-activated cell sorter) used to sort out the white cells from these healthy twins? Did you use something else?
Klein: We used the cell separator, but they may have used the FACS to analyze what kind of cells these were, and then what happened to them after they were transfused and over time. But actually to collect this volume of cells, and we are now talking about perhaps 10-to-the-10th white blood cells–that is an enormous number of cells–the only way you can do that is with the automated equipment that we had had originally designed to collect transfusable components, such as platelets.
Harden: This takes up back then to what you were talking about before we started the interview, about the platelet separation.
Klein: That is right.
Harden: Perhaps I should ask you to talk about that at this point–and to bring it up to AIDS.
Klein: I just wanted to mention that this particular blood bank (at the NIH) was one of the first to start collecting platelets by platelet pheresis. That antedates my arrival here. It was done by manual platelet pheresis, in which there was a series of multiple plastic bags. You collected a unit of whole blood from the donor, spun it down, separated out the platelets, gave the donor back the red cells and plasma and drew a second unit. Over a period of four hours or so you could get the equivalent of four platelet concentrates from four units of blood drawn sequentially from the donor.
When automated devices became commercially available, we were also one of the first institutions to switch to collecting platelets exclusively with automated devices. By using what is essentially a clinical centrifuge to which the patient’s vein is attached, you can, on-line, at the same time, collect six to eight units of platelets processed from a single blood donor and give every other blood component back to the donor.
By way, again, of history, one of the first instruments, the so-called NCI-IBM blood cell separator, was invented at NIH by Dr. Freireich and an investigator from the IBM Company, so we felt comfortable with this kind of equipment. In fact, some of the nurses who were instrumental in those first studies–for instance, Regina Dowling, who was one of Dr. Freireich’s nurses–worked here for me doing platelet pheresis subsequently. So, we felt comfortable with that. We were using the equipment to collect platelets for transfusion purposes. Then, since we had the instruments available, we were using them to collect a variety of different cells, or plasma, for researchers at NIH. It was very natural to use these for some of the AIDS studies.
Harden: It seems that it was right after we began to understand about the cellular immune system, what a T cell is, what a B cell is, that this disease appears that strikes these components. In looking at it from a hematologist’s point of view, what could you have done if AIDS had struck in 1955?
Klein: I think it would have been a disaster. First of all, one of the other very important discoveries was IL-2 (interleukin-2) or T-cell growth factor, and one of the very important investigators in developing that growth factor was Dr. Robert (Bob) Gallo here on campus. What you probably do not know is that one of the ways he could investigate this was by getting buffy coats that were prepared in the Blood Bank. We removed the white cells from donated units of blood because these small numbers of white cells did not do the patient any good–in fact, they sometimes caused fevers in the patient–and we could easily spin them off. So we would spin them off and instead of discarding them we would offer them to investigators. We never advertised it because the response would be overwhelming. But word of mouth was our best advertising, and Gallo’s laboratory was a large user of these cells. That was a resource that was not available to many other people, so it made (possible) discovery of the ability to grow retroviruses in the laboratory. That was an important contribution.
In the 1950s we could not have done that. We could not have grown these viruses, for one thing, so we really would have been out of luck. As you said, in the 1950s we did not quite know what the lymphocyte did, and we certainly did not know about all the different kinds of lymphocytes and their different functions and roles. I think AIDS would have devastated the population. I am not sure what one would have done with this disease. We did not have any of the tools to deal with it in the 1950s or 1960s.
Rodrigues: I was curious. You talked about the earlier attempt to transfuse cells from identical twins with the child who had severe combined immune deficiency disease. Did it work in that particular case?
Klein: You might have to call Dr. Charles Kirkpatrick. The last time I heard, he was in Denver. But I found an abstract. The case was never totally written up in full form. It was only an abstract presented at the Infectious Diseases (Society) meetings saying that the transfusion did work in terms of helping to clear the fungal infection and reconstituting this patient.
For a patient who has an inherited abnormality, it should have been a very dangerous thing to do. If you take lymphocytes from someone else and put them in a person, you should get graft-versus-host disease. Maybe they did. I do not know. It certainly did not say in the abstract. I hope they did not. Or perhaps they did not because the child was not so immunosuppressed that that was an issue. But that may have been one of the concerns. I simply do not know why no one else was doing that, or why there was no follow-up of this patient, or why it was never published in full form. I dug that case up and it was one of the things that interested me. But by the 1970s we could deal with that, because we could irradiate the cells. We did not have to worry about graft-versus-host disease in identical twins. We could go ahead and reconstitute people if we wanted to without that particular risk. So, I think that that worked, but I do not know if there were side effects or adverse effects.
Harden: You were beginning to see and to collaborate with people on these early AIDS patients, at the end of 1982, and the beginning of 1983. In 1983 you become Director here, and it was also late 1982, early 1983, if my memory is correct, when it dawned on people that the epidemiology was showing bloodborne transmission of AIDS. You had a big meeting in Atlanta in January 1983, and the DHHS (Department of Health and Human Services) Secretary assigned NHLBI (National Heart, Lung, and Blood Institute) to be the lead institute with regard to research on AIDS and blood transfusion. What do you recall about this period?
Klein: Before that several things happened. There was a report from the CDC (Centers for Disease Control), and also by word of mouth, of a case of a baby in California, who was infected by a unit of platelets that eventually was traced back to a man who died from AIDS. The so-called Ammann case, was reported, I think, in December of 1982 in the CDC’s MMWR and subsequently, in April of 1983, in the Lancet. This was a case that I heard talked about of transfusion-transmitted AIDS in a baby. That was subsequently published in April 1983 in the Lancet. But this was being talked about in late 1982.
Then there was the hemophilia story. Having been associated with hemophilia at Hopkins–for a year, I took care of 100 hemophiliacs, the largest number of hemophiliacs in the State of Maryland–and when I was at NHLBI, I had been in charge of the Hemophilia Program, so I had been aware of the tremendous hepatitis problem. At that time, the second leading cause of death in hemophilia was liver disease. The first was bleeding. Our goal as to make more concentrate available, to get hemophiliacs to be able to transfuse themselves at home, because they were dying of bleeding. But I retained an interest in hemophilia. In fact, one of the families that I had taken care of at Johns Hopkins subsequently came to NIH and was being treated by Dr. Ray Shulman. They picked up their concentrate from me in the Blood Bank. So I had kept an eye on the hemophilia story, even though NIH was not doing much, almost nothing intramurally on hemophilia. Ray Shulman was doing a little in the late 1970s, and early 1980s.
But suddenly the hemophiliacs started to be reported, first, with this unusual Pneumocystis pneumonia, and second, when people started to look at them, they found the inverted helper/suppressor ratio. Now, along with the gay men that had been reported, people were starting to talk about hemophiliacs, and there was a case or two associated with blood. I must say in all honesty that in 1982 I was suspicious because of the posttransfusion hepatitis story, because of hepatitis in hemophiliacs, but I was not convinced that this was a transfusion-transmitted disease, not by a long shot. Who can say much about a baby? That baby might have had an inherited immune deficiency syndrome of some kind and become awfully sick and died. Certainly the baby got one unit of platelets from someone who died of AIDS but, after all, there were about eighteen million units of blood components transfused in the United States every year, and 12 million units of red cells. If AIDS was transfusion-transmitted–according to our thinking in 1981-82–and it was like hepatitis, we should have been seeing a lot more of it, and we were not.
Hemophiliacs are an early warning system. Many people have said, “You should have known back then (that blood transmitted AIDS).” But in fact, when I was with the Heart, Lung, and Blood Institute from 1973 to 1975, we were aware that there was some suggestion that blood transfusion caused immunosuppression, long before AIDS. In fact, we let contracts to look at the immune system of hemophiliacs. So it did not surprise me that hemophiliacs would become immune suppressed, and it did not necessarily say to me, “This is the AIDS agent, or the AIDS virus.”
Harden: I have one other question along those lines. What is the incubation period for hepatitis B?
Klein: From the time of infection to the time of clinical disease, maybe six weeks to six months.
Harden: Okay. So with AIDS you are dealing with an entirely different incubation period–this is hindsight again.
Klein: We also knew that you could transmit cytomegalovirus and, under unusual circumstances, you could transmit hepatitis A (through blood products). You can transmit malaria, a variety of other parasites, and bacteria, but all of this was within a matter of days to months. Nothing else was years in transmission that we knew of. To think that there could be such a long period of time before there was any suggestion–and remember we did not have a test–of a clinical disease was difficult to accept. Certainly, in my own mind, it was not proved in 1982, not by a long shot. I know about the meeting. I was not an attendee, but I know about the meeting in January of 1983. I have subsequently seen much of the data from that meeting.
Dr. Bruce Evatt, who was one of the leading investigators at the CDC at that time, was actually a year ahead of me in the Hematology Department at Hopkins, and a close friend. I can remember arguing with him at Dr. Conley’s house, when Dr. Conley had a gathering of his former fellows–I wish I could remember the date, but we can find it out because it was the date of the Osler Symposium at Johns Hopkins–and many of the former fellows came back and Conley had them over to his home. I can remember sitting and arguing with Bruce that AIDS was not proved to be a transfusion-transmitted disease, even though the evidence was awfully suspicious. He had more data than I did, and the lesson there is never argue with someone who has more data than you have. He had the epidemiology from the entire United States at the CDC. So, he felt strongly that it was a transfusion-transmitted disease. I was skeptical, but it smelled a lot like hepatitis, and so I was suspicious.
But I remember what some of the other arguments were. In hepatitis we used to see transmission in institutions. The famous studies were done at Willowbrook, in New York, where they actually gave hepatitis to children, and they justified this by claiming that most of these kids would be infected with hepatitis B anyway from being in an institution. I thought that you ought to be seeing this disease (AIDS) in institutions, and we were not.
Also, there was the issue of needlesticks. There was about a 15 to 30 percent risk of hepatitis B if you were stuck with a known positive needle. Why were we not seeing health care workers, who are stuck with needles all the time, with AIDS? Surgeons? Why were we not seeing dentists? They should be getting AIDS out of proportion to the general population. That was actually looked at, and it appeared that they were not. They did not have a significantly higher number of cases than the general population. So, there were arguments that one could make that this did not look like a transfusion-transmitted, or blood-transmitted disease. Then, there was the data on the other side, which obviously began to mount up. I always mark my own absolute conviction from the publication that the CDC had in the New England Journal of Medicine, (Dr. James) Jim Curran’s publication, on transfusion-transmitted AIDS, which was in January of 1984. I had heard of that manuscript and talked about some of the data before that, so my conviction was actually slightly before the publication date, but it was not in 1982 or early 1983.
Harden: But by the date of that publication you were convinced that there was some sort of agent, even though it had an unusual incubation period and was different, and that it was something new?
Klein: That is right. I thought it was probably a virus.
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