Harper's Education and Early Career (1940s to Early
'50s) |
| FISHER: |
So that brings us up to 1954. At this point, I would like to turn to Dr.
Harper and ask him the same question.
Give us your educational background, what led you into the desire to
study medicine at Harvard, what led you into the field of surgery, and how you
came back to the University of Chicago and became interested in radioactive
materials in medicine. Paul? |
| HARPER: |
Yes. |
| FISHER: |
Go ahead and say anything you would like to about this early part of your
life history. Your birthplace was Chicago, I believe. |
| HARPER: |
That's right. Michael Reese Hospital [on July 27, 1915]. |
| LATHROP: |
Why not Lying-In[, the University of Chicago's obstetrics hospital]? |
| HARPER: |
There wasn't any [Lying-In Hospital]. That wasn't built until 1927. |
| LATHROP: |
I didn't realize that. |
| HARPER: |
I think. Well, I grew up in Chicago. |
| YUFFEE: |
On the south side? |
| HARPER: |
No, on the north side. |
| YUFFEE: |
The north side. |
| HARPER: |
Suburbs, and moved around a bit. My father took a flyer [(looked for a
career opportunity)] in the coke and iron business, so we were in St. Louis for
a while, but he gave that up after a year or so and came back, became a lawyer
in one of the big firms—a lawyer, anyway.
Then I went away to
school in New England. Didn't do anything spectacular there. |
| FISHER: |
But this was at Harvard; right? |
| HARPER: |
No, I hadn't got to Harvard yet. |
| FISHER: |
Hadn't got to Harvard yet? Okay. |
| HARPER: |
I ended up in Milton [Academy in Milton, Massachusetts, near Boston], after
several places, and Milton is sort of a prep school for Harvard, so I got into
Harvard, and survived there.
I had sort of wide interests. I majored
in what was called Biochemical Sciences, where anything in Physics, Chemistry,
Biology, Botany, Mathematics counted as part of your major field. There was
actually one course in Biochemistry by an old gentleman that was hypnotized
[(fascinated)] with blood chemistry and respiration.
Then I got
admitted to Harvard Medical School and didn't do anything very distinguished
there. Actually, when I was in college, I did a project—senior project—with
George Wald,20 who later— |
| FISHER: |
How do you spell that? |
| HARPER: |
W-A-L-D. He later was one of the Nobel people [(Nobel laureates)]—on
visual science. He was the guy that did the major work on visual purple. Then I
worked at the Harvard Fatigue Lab on the visual threshold experiment apparatus
that I built, and finally got published under somebody else's name[, a common
practice when you're just a college student].
In medical school,
nothing much happened. I came here for summer quarter as a surgical extern and,
when I got through, surgery seemed like something that appealed [to me], and I
don't know why, particularly; I liked doing things with my hands.
I
went through the surgical residency back in the good old days when beds were
four dollars a day. Everybody paid their bills.
(laughter) |
| FISHER: |
Maybe they could afford to pay their bills. |
| HARPER: |
They had to, then. The emergency room consisted of one
little room on the fourth floor.
Blood transfusions were handled in
a different way. You'd cross-matched the donors ahead of time and had them
waiting in the emergency room, and then, if the patient needed blood, you
dropped out of the operation, went down, and drew the blood and brought it back
upstairs. Quite different. |
| FISHER: |
Interesting. |
| HARPER: |
That situation evolved some. There was an icebox that people would draw
blood and keep it in. Blood donors who were menstruating women were sought after
because their blood settled out very rapidly. You could draw the plasma21
off and use that.
By the end of my internship, the [Second World]
War was going on, and I got involved with a group that wanted to be one of these
[military] unit hospitals. I got started off down in Texas at an Air Force
station hospital, and then, gradually, the people that had recruited us got
shipped elsewhere.
We got shipped all over the world. I ended up in a
clearing company, first in Alabama, and then, France. |
| FISHER: |
And you were married at this time. |
| HARPER: |
Yeah, I got married the last year of medical school. |
| FISHER: |
Did your family accompany you on these assignments? |
| HARPER: |
Not to Europe. But they were in Texas and in Alabama.
Then I
got back here after the war, and resumed a surgical residency, which involved
spending a year in the laboratory, to start with. The idea was—this is an
old-fashioned idea—you got your fingers wet in the laboratory and got a
project going. Then, you could keep it going on the side during the rest of your
residency. |
| LATHROP: |
Maybe we should tell them about the philosophy of the University of
Chicago? |
| HARPER: |
What was that? |
| LATHROP: |
Well, that you—everybody was supposed to do some research. |
| HARPER: |
Well, but the philosophy was that it was a full-time organization. You
practiced on a salary, and you—it was a group practice. For a long time, it
was very unpopular with the surrounding physicians, because it was "corporate
medicine," which was anathema in those days. |
| FISHER: |
But not only was it "corporate medicine," but there was a strong
research component. |
| HARPER: |
Oh, yeah. And they didn't pay you much. They would give you a bed, and they
gave you food, and the chief resident got 200 dollars a month and made money on
it [(covered his other living expenses with a few dollars to spare)].
(laughter) |
| HARPER: |
I worked in the laboratory on various odd things that drew Dr. [Lester]
Dragstedt's22 interest, which involved a lot of dog surgery. |
| FISHER: |
It was in his lab that you became interested in radioactive tracers.23 |
| HARPER: |
That was after I got—I think—yeah, it was after I was in my
clinical residency.
Katherine mentioned Bill Neal, who got sick of
counting rat bones for alpha particles24 over at Site B and came
over and was going through the same residency that I was. We worked together a
fair amount.
He had the experience over at Site B of radioactivity,
and I had some physics background that I picked up in college.
I took
a course in—I don't know what kind of physics it was—atomic physics—Bainbridge
and Street25 [(then the leading researchers in atomic physics)].
Bainbridge is the mass-spectrometer26 man, and that was interesting.
So I knew a little bit about this sort of thing, and I learned more by osmosis
[(just by paying attention)]. |
| LATHROP: |
When did Dwight Clark27 start working with 131I [(iodine-131)]? |
| HARPER: |
That was a separate enterprise. My first clinical year [of medical school]
was with Dwight Clark. [During medical school,] we were with one surgeon for a
year, then another surgeon for a year, and so forth. That has changed, too, of
course.
Dwight Clark had spent two years down at Oak Ridge28
during the war and he came back all hot [(excited)] about 131I [for therapy of]
carcinoma29 of thyroid and thyroid disease. |
| FISHER: |
He had been training at the Oak Ridge Institute of Nuclear Studies, ORINS.30 |
| HARPER: |
I don't know what he had been doing. He had been down at Oak Ridge,
operating with isotopes in a big way. He managed to collect a huge stable of
patients with carcinoma of the thyroid from all around the Midwest and the rest
of the country, and, ultimately, when he died of hepatitis, and I inherited his
stable [of patients] for a while.
So I had all these patients with
carcinoma of the thyroid that we treated with radioiodine, and also the patients
with hyperthyroidism.31 That was a clinical operation.
In
the laboratory—in Dr. Dragstedt's laboratory, I had become interested in
lipid [(fatty substances)] problems because of the type of experiment Dr.
Dragstedt was doing with depancreatized32 dogs, about fatty livers
and this sort of thing.
Our first experiment along those lines was
looking at the turnover33 of a phospholipid34 labeled35
[with] 32P [(phosphorus-32)]. That didn't seem to lead very far. Then, Bill Neal
suggested using carbon-14.36 So we discovered that acetate37
is a general precursor for all sorts of things in the body. So we got some
barium carbonate from Oak Ridge and manufactured our own acetate and injected it
into dogs and drew [their] blood and looked at the metabolites.38
One of the big experiments we did was to take repeated substantial liver
biopsies from a dog who had been injected with acetate. Then we fractionated39
the lipids—[separating them into] free cholesterol, bound cholesterol,
phospholipids, free fatty acids—the best we could with ordinary,
unsophisticated clinical laboratory methods. These residues that we ended up
with, we oxidized and collected the CO [(carbon monoxide)] in little planchettes40
and counted them in a flow counter, a Geiger counter41 we made
ourselves, and ended up publishing it in the first issue of Metabolism.
That was really pretty unsophisticated.
Some biochemist repeated
these experiments later, and, when he was halfway through, he discovered what we
had published and abandoned it. We scooped him [(did the research first)].
(laughter) |
| FISHER: |
Oh, that's interesting. |
| YUFFEE: |
I wanted to backtrack one question that I was interested in. I noted in one
of the biographical sketches that was sent to us that your grandfather[, William
Rainey Harper,] founded the University of Chicago. |
| HARPER: |
With Mr. Rockefeller's help.42 |
| YUFFEE: |
Right. And I was curious as to why you chose to go away to school—to
Harvard. |
| HARPER: |
I've always sort of retreated from that situation [(my grandfather's
involvement with the University of Chicago)]. I don't read his biographies and
that sort of thing. |
| YUFFEE: |
And so did you sort of feel like you were eventually going to come back
here? |
| HARPER: |
No. |
| FISHER: |
So that was a— |
| HARPER: |
Just did. |
| YUFFEE: |
Not a conscious thought. |
| HARPER: |
That's sort of the way I drifted into medicine, because it was an easy
transition from what I had been exposed to in college and that sort of thing.
|
|
Harper's Thoughts on the Mixture of Medicine and
Science (Late '40s and '50s) |
| FISHER: |
You've always been a scientist, as well as a physician, Dr. Harper. |
| HARPER: |
Yes, that's correct. |
| FISHER: |
What did you find more interesting, the science and the research or
treating patients? Or did you enjoy a healthy mixture of these activities? |
| HARPER: |
That's a good way of phrasing it. |
| FISHER: |
When Dwight Clark came back from Oak Ridge and you worked with him on the
iodine-131 thyroid therapy— |
| HARPER: |
Yes. |
| FISHER: |
—was there concern for the irradiation of children or infants in
utero?43 |
| HARPER: |
Dr. Dragstedt was interested in this. He treated some dogs with healthy
doses of radioactivity, pregnant dogs, and the baby dogs turned out to be
classical cretins.44 He had their skeletons around, looking
cretinous, in a glass case in the corridor outside his office for a long time,
so that— actually, it was through Dr. Dragstedt that I got interested in
radiation therapy.
He had a patient with carcinoma of the pancreas45
that was inoperable, and we [surgically] exposed it [(the pancreas)] and planted
radium needles in it. There were strings on the ends of the radium needles,
brought out through a drain. After the appropriate time, we pulled them out, all
but one, and we had to go back [in] after that [to find the missing radium
needle]. |
| FISHER: |
The suture broke or something. |
| HARPER: |
Yeah. So the conclusion from that was, there must be a better way, and I
was directed to find a better way. That's when I developed the tubing—plastic
tubing that you could sew in, following the radium rules, and then you could "afterload"46
it. |
| FISHER: |
That was an early application of a new technology called "afterloading."
|
| HARPER: |
Yes. I hadn't heard of afterloading before that. I don't know if it's the
first instance of it or not. |
| FISHER: |
This tube wrapped around the pancreas? |
| HARPER: |
Yeah. |
| FISHER: |
As close as you could get it, I guess. |
| HARPER: |
No, you—the tubing was PE-10 polyethylene tubing, very fine, like a
suture. It had a piece of wire with the end tapered off, so I could thread the
tubing onto it and sew it around. So it went around and around, with about a
centimeter spacing, and then back and forth through the middle, using the
approximately correct distribution. You probably saw pictures of them in the
prints [that were published in our paper].(47) |
| FISHER: |
Yes, I've read that paper.48 |
| HARPER: |
And then filled it with mercury and radiographed49 it to get
some idea of the volume so we could calculate how much iodine to put in. We
ignored the beta radiation50 from the iodine, and we calculated the
dose on the basis of the gamma radiation.51
Getting it in
was rather tricky, because you didn't want ends loaded with radioactivity
sticking out on the skin. That happened to us once, and we got a nice beta burn
like that on the abdominal wall. It healed up all right. |
| FISHER: |
Was there—were all your subjects of these early investigations people
with disease? |
| HARPER: |
Oh, yeah. I mean, for therapy. Of course. |
| FISHER: |
And was there a reasonable expectation that these new attempts would be
better therapies than anything else previously? |
| HARPER: |
Well, there was no alternative therapy [at the time]. |
| FISHER: |
There was nothing else other than that available? |
| HARPER: |
I mean, with carcinoma of the pancreas, it was pretty-well shown that
surgical excision [(cutting out)] didn't get you very far. |
| FISHER: |
Because you couldn't get all the tumor. |
| HARPER: |
That's right. |
| FISHER: |
And you still needed to leave some pancreas in the patient. |
| HARPER: |
No. You don't need to worry about that. It had to be treated. No, the
tricky part of that was getting 100 millicuries of 131I into a couple of tenths
of a milliliter.52 |
| FISHER: |
Of tube. |
| HARPER: |
Well, in a centrifuge tube.53 And then, we sucked it in, stood
back at the other end of the tube that was full of mercury, and sucked out the
mercury. |
| FISHER: |
I see. Ah, yes. |
| HARPER: |
And then the activity got sucked in, precipitated54 the iodine
with a carrier as potassium iodide (KI),55 silver iodide, and then
dissolved it in saturated KI. That way, we could get the activity on a very
small volume, suck it into the tube.
Where were we? |
|
Lathrop's Early Cancer Therapy Research |
| FISHER: |
Katherine, were you involved in this early study? |
| LATHROP: |
Yes. |
| FISHER: |
Can you give some of your perspectives on this early work in cancer
therapy? |
| HARPER: |
We made a model of the implanted tubing. We made some attempt to measure
the radiation dose inside it. |
| LATHROP: |
Yes, and I spent hours at the microscope, taking readings of density across
the film that had been exposed to that. |
| HARPER: |
Oh, that was something— |
| LATHROP: |
It was part of this, I thought, in the beginning. |
| HARPER: |
That was part of the yttrium pellets. |
| LATHROP: |
I thought it started with the iodine, but maybe not. |
| HARPER: |
Maybe it did. |
| LATHROP: |
Anyway, it was all the same sort of technique. It was very tedious work,
getting information for what the radiation dose was. |
| FISHER: |
How did you calculate the dose from that unusual iodine distribution around
the pancreas? |
| HARPER: |
Katherine did it. |
|
|
Harper's Early Determinations of Radiation Doses |
| FISHER: |
Did you do that work? |
| HARPER: |
Yeah. That was easy. You used the radium tables and scaled the numbers down
from eight rads per hour to whatever it is, three-tenths of a rad56
for the gamma [from iodine-131]. |
| FISHER: |
By radium tables, you're probably referring to the Paterson-Parker tables?57 |
| HARPER: |
Yeah, that's what we used, not the Quimby.58 |
| FISHER: |
It's interesting to me that you began working with gold-198 around the same
period of time. |
| HARPER: |
Well, that was fashionable, and— |
| FISHER: |
Yttrium-90 pellets. |
| HARPER: |
Yes. |
| FISHER: |
Which was fairly unusual for that era. |
| HARPER: |
Yeah. We started that work, I think. No, that was—Dr. [Austin] Brues
was doing something out at Argonne with animals and radioactive pellets. |
| LATHROP: |
You would have to look back through the ANL reports, I guess, to see. I
don't remember that. |
| HARPER: |
Anyway, that was a bright idea that occurred to us, that if you planted
beta sources in a tissue, it would produce a necrotic59 lesion.60
You didn't have to worry about the radiation dose, because you couldn't kill
anything twice. [(Necrotic tissue is already dead.)] The [radiation was
attenuated] so you ended up with a very sharp border of the lesion. |
| FISHER: |
Were these pellets retrieved or left in place? |
| HARPER: |
Oh, left in place. |
| FISHER: |
Allowed to decay out? |
| HARPER: |
Yes. We started off with the neurosurgeons on this. They exposed the
pituitary61 through a frontal flap.62 The idea was that,
if you see what you're doing, you can put the [pellets] in just right.
It turned out that that's a mistaken notion. Once you put a pellet in, you
can't see it anymore, and to place the pellets under vision turned out to be a
disaster.
Then we thought of doing it transsphenoidally,63
and developed instruments to go in through the nose, through the sphenoid sinus64
into the pituitary fossa.65 This worked fairly well, except that it
was difficult, again, to get [the pellets] placed correctly. |
| FISHER: |
Exactly where you wanted them. |
| HARPER: |
Although it was done under x-ray control. That worked moderately well. We
got a few good results, but we did get some patients where the ocular motor
nerves66 got damaged, because they're lying in the cavernous sinus,
right next to the pituitary [gland]. |
| FISHER: |
Did that discourage further work in this area? |
| HARPER: |
No, we switched to a strontium-90 source on the tip of a needle, [which we
developed]. We put that in [transsphenoidally], one applicator on each side.
[The source] contained, nominally, about 100 millicuries of strontium-90 [each].
Constructing those, I developed a wrinkle in my thumbnail. It grew out after a
while. |
| FISHER: |
That leads me to the question of radiation protection of yourself and
coworkers. You worked with a lot of radioactive sources. And you also worked
under conditions with x-ray fluoroscopy,67 I would assume. |
| HARPER: |
The fluoroscopy [doses] were trivial, because we could step back from the
fluoroscoping. It was one of these little C-arm things [(a swing-arm with two
articulated hinges, like a dentist's lamp)]. |
| FISHER: |
But the beta sources were hazardous. |
| HARPER: |
We worked with them under water whenever possible and in little shielded
containers. A few millimeters of lead is sufficient for that. It stopped
everything but the bremsstrahlung.68 |
| FISHER: |
Did you keep track of your radiation exposures during this time? |
| HARPER: |
I didn't. I'm sure the radiation protection people did, the film badge69
people did. I just couldn't worry about it too much. |
| FISHER: |
Katherine? |
| LATHROP: |
I never worked where we didn't wear film badges. |
| HARPER: |
No, the only objective effect I ever got was [radiation damage to] my
thumbnail. You were asking about children with 131I. |
| FISHER: |
Yes, we did really— |
| HARPER: |
You saw the blurb that Alex Gottschalk70 wrote, where he
mentioned the great discovery that Dr. Gottschalk and Dr. Dwight Clark made with
babies. |
| FISHER: |
Yes. It's on the first page. |
| HARPER: |
How to tell the cretins from mongols [(mongoloids)]71: a
millicurie dose of 131I, [and surveying the baby's thyroid with a Geiger
counter]. That was pretty horrendous.
Actually, one of the things
that stimulated me to look into the nuclear medicine applications was the
discovery somewhat later—when they developed crude scanning instruments—that
a thyroid scan with 131I caused a good many rads, which seemed out of line
[(doses too high for acceptable patient diagnostics)].
Dwight Clark
had tumbled to the fact that most of his children [patients] with carcinoma of
the thyroid had had previous radiation for [shrinking] tonsils or adenoids or
[thymus]. |
| FISHER: |
Were these x rays or radium [(the radiation source)]? |
| HARPER: |
Those were x rays. |
| FISHER: |
X rays? |
| HARPER: |
Yes. I think something like 12 out of the first 13 juvenile cases [of
thyroid carcinomas] had had previous radiation. |
| FISHER: |
Was that Dr. Clark [who made the discovery]? |
| HARPER: |
Dwight Clark, yes. |
| FISHER: |
Okay. |
| HARPER: |
So he pushed that, and somebody in Buffalo[, New York] did a prospective
study on this. I've forgotten his name. It showed that people that have
radiation to the neck region got lots more thyroid lumps, and some of them have
gotten thyroid malignancies [(cancers)] some years later. We didn't do that.
Anyway, the only disaster that happened to me in that situation was
a lady with carcinoma of the thyroid that we were treating with radioiodine, and
she got hypothyroid.72 That's normal.
And then, she
stopped having periods [(menstruating)], which was normal with hypothyroidism.
Then she turned out to be pregnant, and the baby was definitely damaged. That
was the only disastrous experience I had with the radioiodine. |
| FISHER: |
Did that lead to any changes in practice? What was the ultimate benefit of
these observations? |
| HARPER: |
Well, you worry more about dealing with pregnant people because, once it
[(harm)] has happened to you[r patient], that's how medical
prejudices get formed; [they are] not [made] on a rational basis. [But] because
of the bad things that happen to you, you swear [it] will never happen again. |
| FISHER: |
How did that change your procedures in the future or in that time? |
| HARPER: |
We worried more about pregnancy [in patients], of course. |
| FISHER: |
Was there ever a study done on the uptake of iodine in the thyroid of
unborn children? |
| HARPER: |
I'm not sure how you would go about doing that. |
| FISHER: |
Well, for example, if a woman was diagnosed using iodine-131 during a
period of pregnancy, was there any evidence of children being born without
thyroid function? |
| HARPER: |
Dr. Dragstedt's dogs are the only thing I was aware of. |
| FISHER: |
Okay. |
| HARPER: |
We had some episodes with people lactating and iodine comes out in the
milk.
Anyway, as I said, I was horrified at the cost of a thyroid
scan in terms of rad[iation dose], and started looking around at other
alternative possibilities. And there, sitting in the isotope table was 125I, and
everybody ignored it because of the long half-life [(60 days)].
But a
few quick calculations showed that the total energy dissipation73
was about the same as with 131I. |
| FISHER: |
I knew it was close to that. |
| HARPER: |
Yeah. So that, in theory, you should be able to get by with a lower
radiation dose, because of the biological dissipation of the isotope. We pushed
that [idea] for a while before we discovered that 131I betas and 125I Auger
electrons were bad things. |
| FISHER: |
You were one of the first to use iodine-125 in the clinic. |
| HARPER: |
Yes. |
| FISHER: |
And, in fact, the— |
| HARPER: |
We didn't [actually] use it for anything but experimental purposes. We
didn't really use it in the clinic; we used it for human studies. There's a
difference. |
| FISHER: |
Okay. And can you amplify on that just a little bit more? |
| HARPER: |
We thought, here we have a wonderful isotope that we can study for a long
time, and the radiation dose is considerably lower than with 131I; and we ought
to be able to do something with it. So we tried doing some things with it. |
| FISHER: |
In a typical experiment, how did this take place? Did you choose normal
subjects for these studies? |
| HARPER: |
Volunteers. |
| FISHER: |
Volunteers? |
| HARPER: |
[We] showed them what we were doing. |
| FISHER: |
Were they paid? |
| HARPER: |
Usually not. |
| FISHER: |
How do you recruit such volunteers? |
| HARPER: |
Friends and acquaintances, usually. |
| LATHROP: |
Ourselves. |
| HARPER: |
(smiling) Captive personalities are much easier to manage. |
| FISHER: |
So were you ever the subject of your own 125I thyroid experiment? |
| HARPER: |
I'm sure I was. I don't remember. |
| LATHROP: |
We both were. |
| FISHER: |
Katherine, you, too? |
| LATHROP: |
(nodding) |
| FISHER: |
The nod probably doesn't record.
(laughter) |
| LATHROP: |
(smiling) Yes, sir. |
| FISHER: |
For the benefit of the transcriber, that was a "yes." |
