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Oral Histories

Medical Physicist Kathering L. Lathrop and Physician Paul V. Harper


Foreword

Short Biographies

Lathrop's Education and Early Career (Manhattan Project, 1945-46)

Lathrop's Work at Argonne National Laboratory (1947-54)

Lathrop's Work as a Chemist at the Argonne Cancer Research Hospital (Beginning in 1954)

Harper's Education and Early Career (1940s to Early '50s)

Harper's Thoughts on the Mixture of Medicine and Science (Late '40s and '50s)

Lathrop's Early Cancer Therapy Research

Harper's Early Determinations of Radiation Doses

Development of Iodine-125 Production Methods and the AEC Review Process

Discussion of Radiation Research Standards

Lathrop and Harper Collaborative Research (1965-67)

Thallium Research

Antifibrinogen Research

Various Radioactive Isotope Research by Lathrop and Harper

Argonne Cancer Research Hospital History (Early '70s)

Research on Brain Tumor Imaging Agents

Collaborative Metabolic Studies

Selenium Tumor-Imaging Studies (Early '70s)

Other Isotope Research

Alpha Emitter Studies Using Radioactive Isotopes

Difficulties Involved With Using Human Volunteers


Development of Iodine-125 Production Methods and the AEC Review Process

LATHROP: Our principal contribution concerning 125I was that we developed the production method.
FISHER: Which is still used today, I understand. It's the same chemical principle.
HARPER: Yeah, that's right.
FISHER: The same radiation principle, using xenon-124.74
HARPER: Yeah, that was sort of interesting. We just froze the xenon into a capsule, a zirconium capsule, which Argonne Laboratory insisted on making, because it was going into their reactor.

We were able to get about ten grams of xenon in by freezing it, then sealed it up with a copper O-ring, sealed and bombarded it in the reactor, then brought it back and froze it again and, then, let it warm up slowly while the xenon came off into a tank and the iodine stayed behind on the walls of the vessel, [which] we then washed out, and it was heavily loaded [(irradiated)] with cesium-137 from a different reaction, so we had to pour it through [an acid-phase Dowex-50 column].75
FISHER: Clean it up?
HARPER: Clean it up. And that worked fine. We encountered some people in a European expedition—I think it was at Badgastein76 —that did some experiments with the 125I in rats.

They gave 131I, a couple of hundred microcuries, to rats and completely wiped out their thyroids; histologically,77 we couldn't see any thyroid tissue. 125I, same dose, the thyroid looked beat up a little bit, but it was still distinguishable as thyroid tissue. [With the 125I, most of the radiation dose from the low-energy electrons was dissipated in a cellular colloid.78]
FISHER: You published your work on production and use of iodine-125 in 1961. Looks like it was in ACRH [(Argonne Cancer Research Hospital)], volume 12.
HARPER: It got into the Journal of Nuclear Medicine eventually.
LATHROP: Reports of the work that was done at the Argonne Cancer Research Hospital. Our work would usually go into [the ACRH reports] before we published in the open literature.
FISHER: Was this an annual report of the hospital?
HARPER: Semiannual.
FISHER: Semiannual report, ACRH?
HARPER: Yeah.
FISHER: And so that would appear as a work sponsored by the Atomic Energy Commission.79
HARPER: Right, definitely.
FISHER: Was there—
HARPER: I mean, Argonne Cancer [Research] Hospital was a[n AEC] Laboratory.
FISHER: Right. Was there support by the Atomic Energy Commission for these kinds of projects? Were you totally independent from Washington?
HARPER: Almost totally.
FISHER: Was there review?
HARPER: A one-paragraph write-up of what we were going to do, or what we had been doing. I forget the name of it [(the form)].
LATHROP: I don't remember, either.
HARPER: Nobody argued with us.
LATHROP: Essentially, they gave us money and told us to do something with it, which we did.
HARPER: Yes. It was permanent, free funding. It was great. It was that period [when] we made most of our [scientific] progress.

(laughter)
FISHER: You know, for us younger investigators, we don't have that luxury.
HARPER: I know you don't. We were spoiled.
FISHER: It's very difficult to get funding in basic nuclear medicine research anymore.

Discussion of Radiation Research Standards

YUFFEE: Was there any form of human-use committee at the time?
HARPER: There was one physicist, Professor Lester Skaggs,80 who went over whatever you were planning to do and said it was okay or it wasn't.
FISHER: On what basis would he make that kind of a decision?
HARPER: His own feelings. He was a senior physicist.
LATHROP: You know, Dr. Skaggs is still living. You might want to interview him.
FISHER: Well, it's interesting that he would make these professional judgments.
HARPER: Well, he was stuck—somebody assigned him the responsibility.
FISHER: Who did he work for? Argonne Cancer Hospital?
HARPER: Yes. He was the chief physicist in the Therapy Section of Radiology.
FISHER: I see.
HARPER: Therapy was in Radiology at that time.
FISHER: These questions are of interest now to the President's Advisory Committee on Human Radiation Experimentsation.
HARPER: Yes, I'm sure.
FISHER: So you'll understand why we—
HARPER: Well, there wasn't any FDA [(Food and Drug Administration)]; there wasn't any IRB [(Institutional Review Board)].81 There were just people like this. There were some radiation protection people that occasionally goofed and tracked stuff all over the hospital themselves. It was early in the game.
YUFFEE: Do you remember when Dr. Skaggs started reviewing human use?
HARPER: He was the first one that was around.
YUFFEE: Was this right at the beginning, when Argonne Cancer Research Hospital first opened?
HARPER: Yes, he must have been, because I'm sure he was there then. He recruited [D.B.] Charleston and crew.
FISHER: Were these decisions based on amounts [of radiation] that were not considered harmful?
HARPER: Most of what we were doing was therapy-oriented, so we were dealing with large amounts.
FISHER: Of activity in here?
HARPER: Yeah, this wasn't nuclear medicine territory.
FISHER: It was—
LATHROP: It wasn't until we started working with technetium-99M [(99MTc)] that things—that our orientation [shifted] towards diagnosis.
FISHER: Okay. That's interesting, too. I think that—
HARPER: Well, I mean, the 125I was the—
FISHER: —was diagnostic.
HARPER: Diagnostic. But technetium turned out to be better [for diagnostic purposes], for many reasons.
FISHER: Let me ask a few more questions about some of the experimental research in normal subjects.
HARPER: [In many cases, we were the subjects.]
FISHER: Can you recall different examples of experiments that were conducted in this way outside the clinic, you might say?
HARPER: Outside the clinic?
FISHER: Not involving cancer patients.
HARPER: For instance, the technetium sulfur colloid82 [research] for liver and spleen83 scanning. I was one of the early subjects, and Dr. Gottschalk was terrified [to tell me that] he found a big hole in my liver. It turned out that one of the [photomultiplier tubes] in the camera was out.

(laughter)
FISHER: That would have been of concern, wouldn't it, to find a metastasis84 in your liver?
HARPER: Then there was the one before we had the camera, we had to do scanning. When you breathe, your liver moves up and down, and the scanner moves back and forth, and you end up with [scalloped] lines along the edges. We had a bright idea for this. We would temporarily anesthetize the phrenic nerve85 so the diaphragm on the right side wouldn't move. That worked. We abandoned that when we found one of our technicians trying to explain to one of the radiology residents how to inject the phrenic nerve.

It was interesting. We could make the liver hold still on the right side, but the left lobe moved more to compensate.

The spleen was really jagged in these studies. That's the sort of thing that we tried to do. There were some other things that we got involved with in connection with the therapy—brachytherapy.86

We had the bright idea that, if you used a low-energy emitter like cesium-131, then the radiation outside the region that you're trying to treat will be reduced, so we looked at that, and palladium-103.
FISHER: Cesium-131 because of its low-energy photons.87
HARPER: Yeah. We never treated anybody with cesium-131, but we used palladium-103 in people who had advanced tumors that needed therapy.
FISHER: Had palladium-103 been used before?
HARPER: I don't think so.
LATHROP: The production of palladium-103 was done in two ways. With the Oak Ridge National Laboratory cyclotron.88
HARPER: It was also done in the MTR reactor89 out in Idaho. That had a lot of carrier palladium with it, and the procedure we called "tattooing the tumor" with palladium black.

Then we tried to get rid of some carrier palladium. We irradiated rhodium targets in the big cyclotron at Oak Ridge, and that was quite an adventure, too. We had to develop equipment for getting the palladium out of the rhodium target. I don't know if that ever got written up in detail.
FISHER: You know, one of the other interesting things that you've done is, you've used beta radiation as a technique for pain relief.
HARPER: Oh, that. Well, that was the same needle that we were using to destroy the pituitary.90
FISHER: Was it? Was that yttrium-90?
HARPER: No, that was strontium-90.
FISHER: Strontium-90?
HARPER: Yeah. The strontium needles, you could stick those in percutaneously,91 [under x-ray control], and lay it against the spinothalamic tract or the anterolateral92 portion of the spinal cord.
FISHER: These were only used in terminally ill cancer patients?
HARPER: The alternative was cordotomy.93
FISHER: Right.
HARPER: And cordotomy in patients of that sort had a substantial mortality. This approach was abandoned because the lesions that were produced [by radiation] tended to grow a little bit and cause trouble.
FISHER: Paralysis?
HARPER: Yes. Neurologic94 defects. So what the neurosurgeons ended up doing was using the same approach, anatomically, but using electrical lesions, which were more localized and didn't grow. That worked better.
FISHER: You mentioned that these experiments were conducted before there was an FDA [(Food and Drug Administration)] that regulated radioactive materials.
HARPER: Well, yes. The Atomic Energy Commission had responsibility for radioactive pharmaceuticals.95
FISHER: What level of oversight was there at the Federal level at this time?
HARPER: Dr. Skaggs.
FISHER: Dr. Skaggs at the hospital?
HARPER: Yes.
FISHER: And really nothing else in Washington[, D.C.]
HARPER: We wrote up what we did and sent it in.
FISHER: Was there feedback and response?
HARPER: None.
FISHER: Oversight, review?
HARPER: None [that we were aware of].
FISHER: To what would you attribute that? Just lack of experience in radiopharmaceuticals?
HARPER: [The use of radiopharmaceuticals] was just growing. Take the kids that Dwight Clark treated [with iodine-131, to see if they were cretins or Down's syndrome victims]. That's one end of the scale. Gradually, regulation grew.
FISHER: Was the University of Chicago considered a training ground for other physicians?
HARPER: Of course.
FISHER: Or did you work quite independently?
HARPER: What do you mean?
FISHER: Did you have a lot of interactions with other physicians and teach these techniques that they then took to their [practices]?
HARPER: Not particularly. I mean, we published, and if people were interested, they followed [the procedures].
LATHROP: Well, we always went to the Society of Nuclear Medicine meetings.
HARPER: Yes, but actually, a lot of [the technology] went to Europe. The Europeans were much less inhibited about plunging into new things than the people in this country.
FISHER: How well were these techniques received by your peers?
HARPER: They sent us patients.
FISHER: They sent you patients? And, in general, how successful was radionuclide96 therapy in, let's say, the 1950s to the early 1960s?
HARPER: The radiologists,97 the therapeutic radiologists,98 were much more interested in doing things with their machines.
FISHER: "Machines," meaning x-ray machines?
HARPER: Yes. And if I wanted to fool around with isotope therapy, [that was my privilege], but I always tried to involve them [(the radiologists)], because it was therapy. They gave up on me and let me do what I wanted, pretty much. I would explain what I was doing [and they would say,] "Fine."
YUFFEE: In regard to when you treated patients—and listening to this, being a lay person, the terminology often goes over my head.
HARPER: Yes.
YUFFEE: So the idea of informing them as to what you were doing, must have been a difficult task.
HARPER: No. You would tell them what you wanted to do; no big deal. I mean, if the patient got cancer, you're going to try to treat it. There isn't any alternative.
YUFFEE: Mm-hmm. Did you explain that?
HARPER: Of course.
YUFFEE: And you would explain the idea of, say, using the strontium needle?
HARPER: Sure.
YUFFEE: And what it meant?
HARPER: Of course.

Lathrop and Harper Collaborative Research (1965–67)

FISHER: Probably the contribution to science that both you and Katherine will be remembered for [is the] development of technetium-99m pertechnetate.99
HARPER: Right.
FISHER: —as a diagnostic agent in nuclear medicine. And now there are something like 35,000 separate procedures [every day in the United States].
HARPER: I know. We never patented it.

(laughter)
FISHER: Mallinckrodt100 appreciates that.
HARPER: I went to a big meeting in Rome[, Italy] just when I was all [excited] about 125I and talked about 125I, presented a paper and sat next to Jim Richards from Brookhaven101 on the plane. He tried to sell me on this wonderful stuff that they had developed at Brookhaven.
FISHER: Which was what? What stuff?
HARPER: Technetium-99m, what else? I didn't hear a word he said. A couple of years later, two things happened: one of our friends was interested in a short-lived isotope for looking at things going through the heart; and Dr. Sorensen was interested in liver metabolism.102
FISHER: Which Sorensen was this?
HARPER: Leif.
FISHER: Leif Sorensen.
HARPER: Leif Sorensen.103 He was interested in—what is it called?
FISHER: Well, in the write-up here, it says, "xanthine oxidase."104
HARPER: Yes, that's it. I'm trying to—I'm old enough now so I go blank on things occasionally. Pardon me.

Molybdenum is the cofactor105 for xanthine oxidase in the liver. So he wanted to use radioactive molybdenum [as a tracer for stable molybdenum].

Katherine set him up with the people at Argonne to make some radioactive molybdenum for him to study,. He studied it and was concerned about the technetium daughter,106 [which] was sort of a nuisance.

He actually [obtained] a blood disappearance curve of technetium, and [determined that] the molybdenum localized in the liver and decayed to technetium, which stayed in the liver.

So he had a project for looking at the—imaging the liver with technetium as the daughter of the molybdenum that was [localized] in the liver. This [research] didn't appeal to me very much, because there's a lot of high-energy gamma from the molybdenum that [obscured the image]. I asked Sorensen [whether,] if he was [not] interested in the technetium itself, could we work on it? He said, "Sure, go ahead," and we were off and running.
FISHER: Now, that leads me to a next question. What happened to the work under [Jim] Richards at Brookhaven?
LATHROP: He made the generators. [(molybdenum-99/technetium-99m generators)]
HARPER: Yeah. He was the supplier of generators for years.
FISHER: So he built your generators and you applied them in the clinic [(Argonne Research Hospital?)].
HARPER: That's right.
LATHROP: They had a whole group that was working on making generators. Remember, down at Oak Ridge one time, we spent half the night talking with two people [from the group]. I forget their names.
HARPER: Yes.
LATHROP: And we were told to be quiet after a while.

(laughter)
LATHROP: Well, that was because—
HARPER: —that's because we had a bottle of whisky.
LATHROP: That was because of the cardboard walls in the hotel. [(People in the next room would be disturbed.)] But, anyway, they had a whole collection of generators.
HARPER: Yeah, iodine-132, and there were a variety of other things that they developed. But the technetium was the one that flew [(was successful)].
FISHER: It sure was.
HARPER: Unfortunately, the technetium that came off the generator was slightly contaminated with iodine and with various other things.

Mrs. Lathrop dug out some literature from Russia in The Proceedings of the Peaceful Uses of Atomic Energy, [that explained] separating technetium and molybdenum using methyl-ethyl-ketone [(MEK, an industrial cleaning solvent)] extraction from sodium hydroxide.

So, after that, we just bombarded the molybdenum oxide in the local reactor, and it dissolved in [sodium hydroxide] which reacted with [molybdenum oxide.]
FISHER: Was that the Argonne reactor?
HARPER: Yes, CO-5 reactor. We even constructed a big, fancy apparatus to do it remotely, more or less.
FISHER: That's amazing.
HARPER: We supplied the clinic with technetium [as pertechnetate for thyroid studies] and started looking at the other applications of technetium. We knew it stayed in the liver when it arrived on the scene from molybdenum in the liver, so we thought there must be some way of making it stick in the liver.

We found a preparation, technetium thiocyanate, [that] was soluble in fat. And so we were injecting it mixed with fat emulsion. It all ended up in the liver, and that was a temporary solution. The actual solution which we ended up with, [was developed by] Jim Richards [at Brookhaven.]

We told him we would like to have technetium in a colloidal form that would [localize] in the RE [reticuloendothelial]107 system.
FISHER: For liver scans, for example?
HARPER: Yeah, for liver scans, [spleen, and] bone marrow.108
LATHROP: Both he and Hal Atkins109 came to visit us, and we were discussing all these things. I said I tried using sulfur colloid, but I couldn't get any kind of sulfur to precipitate [with hydrogen sulfide], but I couldn't get any precipitate that I could recover.

So they went back home. It was less than a week when they called us and said that they had used this same method; they had added gelatin to the preparation [to make the process work].
HARPER: Yes, as a protective colloid.
LATHROP: You know. And they had been able to [produce] something that they thought could be used.
HARPER: We put it in a mouse, and it stayed in his liver, and, I think, a few days later, we [tried it in a human subject]. It stayed in his liver. The alternative was gold-198 [colloid]. So, [we had developed a method with technetium that vastly reduced] the radiation dose.
LATHROP: There had been a horrible episode [elsewhere], where someone had given 198Au [(gold-198)].
HARPER: [In error.] Millicuries instead of microcuries.
HARPER: We got the patient, eventually. I think he or she didn't survive. Anyway, we were [particularly concerned] about this. The procedure was to bubble hydrogen sulfide through IN (normal) [(pH-neutral)] HCl [(hydrochloric acid)] containing the pertechnetate and [gelatin]. It formed a colloid with the gelatin, [carrying the technetium], which was then diluted so that the acid concentration wasn't too high to give intravenously.
FISHER: Katherine, did you do these preparations?
HARPER: We all did them.
FISHER: You all worked together on this?
HARPER: Yeah. I mean, from now on, we're a team. So the way I phrased it was: I provided the ingenuity and Katherine provided the scholarship.
FISHER: Well, you've been collaborating [together] now for more than 40 years.
HARPER: That's right.
FISHER: This sulfur colloid—was it first tested in a patient, or an animal?
LATHROP: We always tested them in mice [before human testing].
HARPER: For the first six months, we didn't dare give it to people without trying it on a mouse first. After a while, we got some faith in ourselves and didn't bother with the mice anymore.
FISHER: When you found good localization, then it was used diagnostically?
HARPER: Right.
FISHER: And by that time, the rectilinear scanners110 or the imaging cameras were sufficiently developed. You could get a pretty good image?
HARPER: Yes. [The cameras came later.]
FISHER: Okay. Now, tell us more about your human studies with technetium-99m.
HARPER: Our first experience with it, we put it in a mouse, and it ended up in his stomach, his bladder, and his thyroid and salivary glands. We said, "My God, what's it doing in the thyroid?"

Then we discovered that the people at NIH111 had been using technetium-99m pertechnetate as a tracer for the thyroid. It's similar to perchlorite and iodide and thiocyanate. It has the same characteristics. They had been using it for physiologic112 studies. We went off pursuing the thyroid.
LATHROP: We also had a reference from someone up at Battelle Northwest,113 I think, who said that it did not localize in the thyroid.
HARPER: I don't remember that.
LATHROP: Yes.
HARPER: Anyway, we had an eager-beaver surgical resident working with us at that time who did a lot of study; this was George Andros.114
FISHER: You know, technetium-99m was a contaminant in the plutonium fuel cycle.
LATHROP: Yes.
HARPER: Of course. Anything long-lived [(with a long radiation half-life)] is.
FISHER: That was a particularly nasty one, because it followed uranium through the gaseous diffusion. Technetium-99 built up in uranium fuels after each recycling of the material; so the concentration grew and grew.
HARPER: I was not aware of that.
FISHER: So there was some concern about technetium-99 exposures of workers. Perhaps that's the reason why some studies were done [on the subject].
LATHROP: I think that's probably it.
HARPER: That could have been.
LATHROP: But somehow or other, they missed the fact that it [(technetium-99)] was localizing in the thyroid.
FISHER: In the thyroid.
HARPER: Well, technetium-99 would be—there might be enough carrier present to suppress the thyroid localization. I don't know. That [study is going to be done] on people.
FISHER: There were a number of experimental studies conducted on technetium in various forms from that point on.
HARPER: That would also be in Katherine's—
LATHROP: I don't think we gave you—did we give them a report of the Oak Ridge —the paper that was given at the Oak Ridge symposium [at Knoxville]?
HARPER: I don't know.
LATHROP: We had—this was back in 1965, I think—
HARPER: Yeah, I think you did. It was—
HARPER: And there is a picture in there that shows the number of organs that were visualized with technetium.
HARPER: Yeah, that looks like it, something that was about that size.
FISHER: What—for the benefit of the transcriber, we're looking at chapter 18, on "Pharmacodynamics of Some Technetium-99m Preparations" by Paul Harper, Katherine Lathrop, and Alexander Gottschalk, spelled G-O-T-T-S-C-H-A-L-K, in the proceedings of the—this is probably the first?
LATHROP: This was the first symposium of the sort. They had—
FISHER: Oak Ridge Institute of Nuclear Studies.
HARPER: Well, I think we presented at in Badgastein[, Austria] before that, in Europe, and maybe even in Athens[, Greece].
LATHROP: Yes, but I understood him to be referring to the publication.
HARPER: Oh, yes.
FISHER: This one is in a publication called Radioactive Pharmaceuticals, available as CONF651111, April 1966, edited by Andrews, Kniseley, and Wagner. [I am referring to] Henry Wagner and [former ORINS director] Gould Andrews, of course, early pioneers in nuclear medicine.
HARPER: Right.
FISHER: And [Ralph M.] Kniseley115 had an interest in both nuclear medicine and therapy. Those are all names that come to mind [when thinking of that field]. You worked with some good people during these years.
HARPER: We didn't work with them. We were all working in parallel in different places.
LATHROP: Well, that shows the number of [human] organs that we had visualized in a fairly short time [using 99mTc].
HARPER: The one thing that we missed was the bone [visualization] agents.
FISHER: Who came along later and developed the bone—the diphosphonates?116
LATHROP: Oh, that was [Gopal] Subramanian.117
HARPER: Katherine's special friend.
LATHROP: That was Subramanian.
FISHER: That was a clever idea, to attach technetium to a bone substrate.118 Did you do additional 32P—phosphorus-32 studies?
HARPER: The only 32P studies we did were the original one with lipids when I was a resident. The only other use we made of it was as pyrophosphate119pellets that we used as flux120 monitors when we were irradiating things in the reactor.
FISHER: Why has it not been used more therapeutically?
HARPER: I haven't the slightest idea.
LATHROP: I assayed121 tissues that were sent to me when I was still at the Manhattan Project122 from children who were being treated for leukemia.123 They were autopsy samples; they [the researchers] were using it that far back.
FISHER: 32P in the treatment of leukemia?
LATHROP: Yes. And then the—
FISHER: Who was using it at that time?
LATHROP: Pediatricians here at the hospital.
FISHER: At the Argonne Cancer—
LATHROP: No, here at the University of Chicago.
FISHER: At the University of Chicago.
LATHROP: This predated the Argonne Cancer Research Hospital.
FISHER: Oh, I see.
LATHROP: This was while it was still the Manhattan Project. They sent me tissue [from] autopsies.
HARPER: Well, was Dr. Jacalin doing it, or—
LATHROP: No. It was a woman pediatrician[, Mila Pierce.]
HARPER: Okay.
FISHER: During the Manhattan Project, using 32P in the treatment of childhood leukemia?
LATHROP: Yes.
FISHER: That's interesting.
HARPER: I don't know where they got the 32P.
LATHROP: Well, I'm not sure where they got the 32P, either, but they were sending them [the tissue samples] to me to assay so they would know what the localization was and, maybe, something about the radiation dose.
FISHER: And how did you do those assays?
LATHROP: It was a beta assay [(an assay to determine the amount of 32P present in the tissue sample)].
FISHER: Using what kind of samples? Blood samples?
LATHROP: No, they were tissue samples.
FISHER: Tissue samples? From autopsies?
LATHROP: Well, there was probably blood, too, but there were other tissues, various [internal] organs.




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