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Harden: Did people give you a reason about why there were not interested?
Klein: We were told by some groups that it was simply too expensive. They did not have the time and the personnel to devote to such an investigation. We were given the impression that it probably was not a very high priority at the time. I was astonished. Of course, we had no problem getting immunologists, and the FDA (Food and Drug Administration) was extremely interested both in the specimens and the data that were coming out of the demographics from these individuals. We learned very quickly what was wrong with some of the questions we were asking. We also learned that about a quarter of our people had gone to donate blood at the Red Cross simply to be tested. We had feared that that would be the case when a test came out. Alternate test sites had been set up. But still people came to be tested. When we asked them why they came to the Red Cross instead of going to the alternative test sites, they told us that it was more pleasant to come to a blood center, and frankly, it was more confidential. So there were a fair number of demographic points that came out of that study. It was a very important study, one that continues. I believe that the freezer full of specimens will also turn out to be valuable as the years go by.
Rodrigues: One other question, not related to AIDS, but you mentioned last time some of the other devices you had. I am always interested in technologies that are developed at NIH. Other than the story that you told us about the blood separator, are there other projects that your department is undertaking in terms of developing new technologies?
Klein: I am not sure that it is new technology, but since the late 1960s blood has been stored in plastic bags–red cells, plasma and platelets. We have studied the platelets here, and many other studies have been done on gas exchange through the plastic. It is a very important subject. When you collect a bag of platelets, they are best stored at room temperature, and you rock them so that there is gas exchange through the plastic bag. When Dr. Steven Rosenberg started doing his studies of LAK cells–that would have been in the early 1980s–he was originally growing his cells in what are known as roller bottles. They are firm plastic bottles. You could only grow limited number of cells. There is no air exchange through the plastic. He has walls and walls of these roller bottles. They are very difficult to work with, and the chances of contaminating the roller bottles when you went into them to change medium was enormous. Dealing with human beings, growing up cells in these bottles, and making a product that you then gave back to human beings, was a very tedious process. At that time people would come to see what Steve was doing and they would leave and say, “We can’t do that at our institution. We don’t have the resources.”
We had an idea, working with Steve. We had been collecting the cells from his patients, and we said, “We store platelets in these bags. Why can’t you store your cells and grow them up and expand them in these plastic bags? It seems to make a lot of sense. They exchange gas very well. If you did that, you could change your medium and put in your additives much the same way we make blood components. You could spin them down in a centrifuge and you could squeeze out supernatants that you do not want. Then you can connect these bags in a sterile manner through their plastic tails without ever opening the system.”
It took quite some time to convince Steve Rosenberg of that, and of course he had to do the studies with his cells in his laboratory, which took even longer. But eventually he agreed that this was the way to go, and it had enormous advantages. All these bags could be processed with our automated equipment. He switched entirely from roller bottles to plastic bags. This had two major effects. First, it allowed him to do much more than he could do previously with fewer resources and with a much greater safety margin. Instead of having 4,000 openings per patient in a system, he was down to a half dozen to a dozen openings, so the risk of contamination was much smaller. The other advantage, certainly for the advancement of that kind of treatment, was that it allowed other people to do it as well. People could come to the laboratory and say, “We can test this in our medial center.” In fact, within a year, NCI had set up half a dozen extramural centers testing LAK cell therapy. It would not have been possible without those bags.
The bag system is now being used for gene therapy and it was used for the first gene therapy patients. We are not using it for growing up the vectors for the gene therapies, all of the cells, for the patients. Sterile docking connections can be made and the risks of infection and losing these valuable biologics have literally disappeared. So I think that was a major contribution coming from blood banking technology being applied to new therapies and new ideas.
Harden: Is there anything else that we need to cover?
Klein: I think in terms of the response to AIDS, I want to emphasize again that we believe that questioning and understanding the behaviors and the demographics of the epidemic are as important as the actual testing part, or screening. We learned from hepatitis, where getting rid of paid donors and then finding out what kinds of things correlated with hepatitis, that questioning and demographics were just as important as testing was. Over the 1984-1993 period we have–as have others–repeatedly updated and improved our questioning. We learned, for example, as did others, that bisexuals do not consider themselves gay. If you had to ask about contact with another man, asking, “Are you a homosexual,” or “Are you a gay male?” were bad questions, and we missed people. We found that out in our prospective studies of donors from the Red Cross, by asking, “Why did you come? You knew that you were a gay male.” The answer was “I am not a gay male; I am bisexual.”
We continually updated our questions as we learned more from these studies. Our actual screening techniques that are in addition to testing have become much more sophisticated and much more effective. That is a very important point, because many people felt that with the test that would solve the problem. It has not. We still have some cases of HIV-infected donors that slip through the tests. We hope that the improved screening techniques eliminate more who would have slipped through the testing.
Harden: What do you see as the future in terms of blood substitutes and other ways to eliminate the very small percentage of HIV-infected donors that still remains?
Klein: What would be ideal is either to sterilize blood from all infectious agents, or find some kind of a substitute for the various components of blood. It is possible now to sterilize plasma, at least there is a research publication on sterilizing frozen plasma, and I believe within the next year, all of the plasma that we use will be sterilized. Commercial companies sterilize a variety of factors for hemophiliacs. We cannot yet sterilize cellular components–red cells and platelets. It looks as if it will be a difficult chore to be able to sterilize those components without affecting the infection of the cells. There is a lot of work being done, but I am not optimistic that within the next several years we will be able to sterilize those cellular components.
Harden: So, how about using an artificial component or stem cell research?
Klein: Stem cell research, I think, is very exciting. Just as we can now grow up all kinds of cells in incubators, it is certainly possible that we will be able to take very early progenitor cells and make all kinds of blood cells. Bear in mind that if you start with a human cell it does not guarantee that you will not have some kind of an infectious agent. Since cell culture systems are ideal for growing viruses–that is how we have done it all these years–viruses could also be introduced. It is not perfect but it is very promising, although again it is a long-term prospect for growing blood for human use. Certainly it is feasible, whereas a decade ago I think everyone would have laughed at the concept. No one is laughing any more.
There are promising substitutes for red cells, that is, components that will deliver oxygen. Molecular technology has allowed us–us being the community and not the NIH–to clone the gene for human hemoglobin and now to produce hemoglobin and grow it up in large vats much like making beer or growing beer. Human hemoglobin can be grown and a couple of tricks have been applied to make the hemoglobin more desirable for transporting oxygen in human beings outside of the red cell membrane. It still remains to be seen as to whether that will be toxic, and there are several groups working very hard on that. My guess is that within the next year to two years either we will have a red cell substitute from the hemoglobin protein, or we will know that we will never have a red cell substitute because the hemoglobin itself is endogenously toxic. But again, five years ago I would have said that we were not going to see any of that in the near future and we will not know the answer to that.
There are also some other chemicals that carry oxygen. At least one of them has been licensed in cardiac surgery for coronary artery surgery, not as a blood substitute, but as an oxygen-carrying radiopaque fluid. Work in that area suggests that perhaps within a couple of years we will have something that at least transiently will carry oxygen and might eliminate about half of the blood we use during surgery, a short-term substitute. Since most of blood in the United States that is used today is still used for surgical procedures, that would be a major step forward.
I do not think in my lifetime that we will have a replacement for the clotting cells, for the platelets. There I think the hope is either to be able to grow them in culture–and I think that is a ways off–or be able to put into human beings early cells that will then become platelets. We are seeing that already in some of our cancer therapy, where early progenitor cells that circulate in the periphery can be collected from a patient, frozen away, given aggressive cancer chemotherapy, and then these progenitors given back. In 10 to 15 days there will be some platelets and white cells from those progenitors, while platelets cannot be frozen very well and white cells not at all. This has not totally replaced the transfused platelets, but it has shortened the period of time in which platelets and white cells are needed from perhaps twenty days, maybe even four weeks, to perhaps five to ten days, which again is a dramatic advance. We have seen the kind of technology that will cut down on the need for transfused blood components and use the patient’s own cells to get them through other procedures.
Harden: Thank you, Dr. Klein, for talking with us.
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