by Lewis Thomas
This, we thought, was surely the way to go. The next step was to inject papain intravenously, in order to reproduce the generalized reaction, kidney necrosis and all. We did this, and nothing happened. The animals remained in good shape, active and hungry, and their kidneys were unblemished. We repeated it, using various doses of papain, always with negative results. But then we noted that the rabbits, for all their display of good health, looked different and funny. Their ears, instead of standing upright at either side, rabbit-style, gradually softened and within a few hours collapsed altogether, finally hanging down like the ears of spaniels. A day later, they were up again.
I am embarrassed to say how long it took to figure out what had happened. I first observed the papain effect in 1947, and examined microscopic sections of the affected ears without finding anything wrong in the cells, fibrous tissue, cartilage, or other structures in the ear, and dropped the matter. Every few months I returned to it, sometimes in order to demonstrate the extraordinary change to friends and colleagues, but never with any sort of explanation. It was not until six years later that it dawned on me that since a rabbit’s ears are held upright by cartilage there simply had to be something wrong with the cartilage plates in those ears. I went back to it, comparing the quantity of cartilage matrix—the solid material between the cartilage cells—in the ears of papain-treated rabbits with normal rabbits, and found the trouble immediately: although the cartilage cells themselves appeared perfectly healthy, almost all of the supporting matrix had vanished after papain. Moreover, the same changes occurred in all cartilaginous tissues, including the trachea, bronchial tubes, and even the intervertebral discs. Parenthetically, several years after my published report on this business, some orthopedic surgeons introduced the use of papain as a method of getting rid of ruptured intervertebral discs without surgery. Beyond this, so far as I know, nothing of any practical value ever emerged from the work on papain, but there were one or two points of theoretical interest, perhaps relating to disease mechanisms.
Papain works as an enzyme only in its reduced state, while the oxidized enzyme is inert. Contrary to our expectations, it was only the oxidized inactive enzyme that worked in rabbits. Intravenous injections of reduced papain caused no ear collapse, nor did the enzyme succeed in getting out of the bloodstream into the cartilage tissue. Only inactive papain could do this, and presumably was then activated by some reducing agent already present in the cartilage matrix. At least two parts of the reaction were under the rabbit’s own control: the transport of the enzyme across capillary walls and then its activation.
There is a long scholarly paper by two sociologists, Barber and Fox, which seems to have become something of a classic, reappearing in several collected reviews of the field, about this papain work, but from a specialized sociological point of view. They had learned from a pathologist friend that another researcher had encountered the papain effect on rabbit ears in the course of enzymological studies on another problem and had failed to follow it up. The sociologists’ problem was to discover why I had done so and he had not. I remember being interviewed in my laboratory at Bellevue, five years after the work, trying to think of why I had been unable to drop the problem, and all I could think of was that it was so entertaining. By that time I had also learned that cortisone had the remarkable property of keeping the ears collapsed, so I was able to justify working on so seemingly frivolous a problem by the possibility that cortisone might possess the capacity to interfere with the synthesis of mucopolysaccharides in tissues—which gave the whole affair a down-to-earth, usable aspect. But I was obliged to confess, despite this, that the work had been done because it was amusing.
15
CAMBRIDGE
In 1959 and 1960, I took a semisabbatical leave from NYU and Bellevue, three summer months each, and went with my family to England to work on the placenta. Sabbaticals are designed not for resting but for getting into new ground for a while. I was looking for a new kind of problem, different from endotoxin and microbial infection, and I had become enchanted by the strange architecture of the human placenta. Also, my associates and I had discovered a few months earlier that enormous masses of this multinuclear tissue, owned and operated by the developing fetus, were constantly breaking off and floating away into the mother’s circulation throughout pregnancy. I was curious to find how this happened and what it meant.
The trophoblast of the human placenta consists of two layers of cells which are the most primitive and at the same time the most specialized of all our cells. They are there from almost the very beginning, soon after the fertilized ovum begins to undergo its successive divisions, forming the bank of invasive tissue which will attach itself to the wall of the uterus and there insert its roots for the future embryo. After implantation, the trophoblast becomes the lining for an immense lake of maternal blood, on which the embryo feeds. From the mother’s immunologic point of view this tissue is, of course, foreign, and the trophoblast is, doctrinally, a homograft.
But it is the most successful of all homografts, surviving throughout all nine months of pregnancy. At the outset it is made up of individual cells with single nuclei, called the cytotrophoblast, but soon after implantation these cells give rise to a second layer of fused cells, containing innumerable nuclei, called the syncytial trophoblast. The syncytium expands and extends, becoming one gigantic single cell comprising the bulk of the whole placenta, the largest single cell in nature. Somehow or other, it is not rejected by the mother—not, at any rate, until the end of pregnancy; perhaps then it is rejected all at once, and the act of rejection becomes the act of birth.
It has been known for a long time that fragments of syncytium occasionally became dislodged from the placenta; small bits of multicellular tissue had been found occluding the small veins and capillaries of the lung in women who died in eclampsia, but it was not recognized that this was a normal event. Our group at Bellevue had learned about this by drawing samples of blood from catheters inserted in the femoral vein up to the level where the uterine veins, draining the placental lake, enter the vena cava. Throughout normal pregnancy, from the sixth week on, this blood contained ten or more multinucleated syncytial masses in each cubic millimeter, each one the size of forty or fifty leukocytes. The fragments looked solid enough in our blood smears, but obviously they must have ways of breaking up into smaller bits or disintegrating altogether soon after entering the mother’s blood; otherwise they would have blocked the circulation of blood in her lungs and pregnancy would be an impossibility. We made the guess—still a good one, I think—that the dislodgement of this mass of fetal tissue is a way of desensitizing the mother, flooding her circulation with so great a load of foreign antigen that her immunologic system becomes “paralyzed,” unable to respond.
I had corresponded about this with Professor J. Dixon Boyd, then head of the Anatomy School at the University of Cambridge, and he liked the general idea enough to invite me over to work in his laboratory. Boyd was at that time one of the leading experts on the morphology of the human placenta, with a large collection of histologic specimens of placental tissue at all stages of pregnancy.
We arrived at Cambridge in May, and found temporary lodgings in a tiny cottage in Grantchester on the grounds of “The Orchard.” Later we rented half of the very large Cornford house at Conduit Head, off Madingley Road, just at the edge of town. Thinking back over the years since those two summers, I have trouble recalling all the day-to-day events in the laboratory, but I can remember every single aspect of the Cornford house—the chickens in the side yard, the garden, the feeling of elation each time I drove up the narrow drive, the special Cambridge sky, the quiet.
I began work in Boyd’s laboratory, trying to set up facilities for tissue culture in hopes of getting live preparations of trophoblast for immunologic study. Within a few days it became obvious that this was going to be a technical problem beyond my competence, and Dixon Boyd proposed that we talk with Miss Honor Fell (n
ow Dame Honor), head of the Strangeways Laboratories, who knew more about the cultivation of cells and tissues than anyone else in town, or anywhere else for that matter. So, one midafternoon I drove out to the Strangeways in a car still half loaded with unpacked bags and went in to see Honor Fell.
She was waiting for me at her laboratory bench, a tall and dignified lady of the old school, very much in command of every detail of the Strangeways research programs, and at the same time totally preoccupied by her own work, which she had always done, and I believe continues to do, with her own hands. She had a capable and alert laboratory assistant, a younger man, whose function was to prepare the materials she was to work with and hand her various items as she worked, but it was clear from the moment I first saw her that Miss Fell did her own research. She may have had an office desk somewhere in her laboratory, but I never saw her at it.
Miss Fell had invented a good many of the intricate procedures for cultivating embryonic organs. The greatest difficulty in this kind of work had been the risk of contaminating the cultures with bacteria from the air or from the investigator’s own respiratory tract, and Miss Fell had worked out a meticulous and nearly infallible technique for keeping her cultures free of accidental infection. By the late 1950s it had become easier to prevent infection by using antibiotics in the tissue culture media—a combination of penicillin and streptomycin was then in general use for this purpose. But not in the Fell laboratory. She used no antibiotics at all, and indeed disapproved of them, partly because they introduced new variables into any experiment, but also, I suspect, because she felt that any careful worker should be able to keep things clean and it was somehow unsporting to bypass the need for such care by relying on antibiotics.
We talked about the placenta for about twenty minutes. I had the impression that Miss Fell was not as swept off her feet by the problem as I was, and not at all confident that it would be a suitable topic for a brief summer’s work, but she was extremely kind to me and offered some helpful suggestions. Then teatime arrived, and the conversation shifted away from the placenta and, with mounting animation, to Miss Fell’s laboratory problems. Chief among these, at the top of her mind, was the cultivation of whole mouse embryonic bones, for which she had worked out a beautiful technique involving the placement of the tiny bones on little doilies submerged in a nutrient medium of great complexity and usefulness. The problem then preoccupying her laboratory was the action of vitamin A on these explants: within a day or so after adding the vitamin, all of the cartilage matrix became dissolved and disappeared, leaving the cartilage cells, still healthy, bunched together in solid clumps. The impression was that vitamin A was somehow inhibiting the production of matrix by these cells, but without doing damage to the cells themselves.
The microscopic slides of the mouse bones were remarkably like those of my rabbits’ ears. By good luck, I had brought some of these specimens along from New York, and they were still in an unpacked box in the car parked just outside, so I brought them into the laboratory and we had a close look at the mouse bones and the rabbit ears, side by side. It was as cheerful a tea as I’ve ever had. By five o’clock we had agreed that there must be a connection of some sort between the systemic action of papain in the rabbit and the local action of vitamin A on mouse embryo bones, and by five-fifteen we had planned the experiment which was to occupy the rest of the summer.
I cabled home the next morning for a supply of highly purified crystalline papain protease, and made arrangements with Professor Boyd for a clandestine allocation of six young rabbits for my use. This was illegal, for I had not obtained a license for animal experimentation in England, but the matter seemed urgent enough for me to risk a penalty; also, I was quite sure that a single experiment with six rabbits would provide all the answer we needed.
During the next few weeks, everything fell neatly into place. Miss Fell added a little papain to her mouse bone cultures, and duplicated the vitamin A effect, while I administered large doses of vitamin A by stomach tube to my rabbits, and their ears collapsed within twenty-four hours. In each case, the microscopic changes in the involved tissue were precisely as predicted.
The almost self-evident explanation was that vitamin A must be causing the release of a proteolytic enzyme in both the mouse bone explants and the cartilage tissues of living rabbits, with the same extremely selective action as papain, removing the matrix without affecting the cells. This would have to mean that a source for such an enzyme, but in its inactive form, already exists in normal cartilage tissue. The best candidates for a source known at that time were the lysosomes, small membrane-lined sacs filled with a variety of hydrolytic enzymes, scattered through the cytoplasm of all cells. These organelles had been discovered a few years earlier by Christian de Duve (who received the Nobel Prize for the discovery) and were suspected of playing a role in the digestive processes of individual cells. Over the next few years, the Strangeways group proved that this was indeed the explanation for the vitamin A effect: the vitamin caused the selective disruption of lysosome membranes and the release of their enzymes, and a protease with properties similar to those of papain then leached away the cartilage matrix, and that was that.
16
THE GOVERNANCE OF A UNIVERSITY
Long ago, in the quiet years before World War II, being chairman of the Department of Medicine (or the Department of Physiology, or Surgery, or whatever) in an American medical school was pretty much like being head of the English department over in the main part of the university. From year to year, the medical school remained the same size, in the same aging buildings. The university shared a fixed portion of its general endowment with the medical school. The latter did its best to secure extra money of its own, but never great sums, from affluent alumni or their patients. The medical school’s budget was a fairly steady sum of money from one year to the next. The main difference between running a major department in the two parts of the university was that many of the key faculty members—the professors—in the clinical departments of the medical school were not paid a salary by either the university or the medical school. These men had their own offices elsewhere in the city where they conducted a private practice and earned their livelihood. The holding of a professorial appointment on the medical school faculty was a mark of professional distinction, carrying some assurance that patients would be referred to the physician-teacher’s care for diagnosis or treatment by other doctors, and the physician-teacher did quite well.
At the time I reached the low rungs of the academic ladder, ready to try my hand at science, money for research had to be scraped together in very small sums, enough to buy rabbits and mice and minor supplies. Technicians were rare personages, to be found only at the benches of the senior-most professors. It was taken for granted that I would be responsible for preparing my own bacteriological media, washing and sterilizing my own glassware, and looking after whatever animals were involved in my experiments. For the first two years of my work at the Thorndike, the costs of all the supplies came to $500 a year, this from a special endowment called the Wellington Fund, which had been bequeathed to the laboratory years earlier.
After the war, the federal government made the decision that science was useful and important, and research within the medical schools became a much more serious business. As a result, the differences between the management of the medical school departments and their counterparts elsewhere in the university became sharper. While the English department continued to lead its more or less steady existence, assured of a fixed complement of tenure and nontenure positions for its faculty, and equally assured of a steady but very modest fixed income from the university’s endowment to pay its costs, the medical school departments, and some of the science departments within the university proper, began to explode. An individual faculty member in, say, the Department of Microbiology, an expert on the streptococcus or meningococcus, could now file an application for a government grant to support his laboratory, purchas
e supplies and new instruments needed for the pursuit of some new ideas, pay part or all of his own salary, and hire one or two technicians. A few years later, whole departments came under grant support, with money enough to recruit new faculty members, provide fellowship funds for increasing numbers of Ph.D. candidates as well as postdoctoral fellows, even money to build new laboratory quarters. And later still, in the 1950s and throughout most of the sixties, the federal research funds arrived in bundles large enough to renovate most of the buildings in existing medical schools and to build more than a score of brand-new schools.
I served as the dean of one medical school, New York University, during the period of rapid expansion and at another, Yale, during the time when the funds were reduced, not yet to a trickle, but to a thin, even flow. Both experiences brought me closer to the inner workings of the modern university than I had ever been before. Being a professor in a medical school is a good way to find out how these highly specialized institutions and their connected hospitals function, but the university itself seems a remote place, almost nonexistent. Being a dean is different: you get to look inside.
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The governance of academic institutions has been considered and reconsidered, reviewed over and over by faculty committee after committee, had more reports written about it than even the curriculum, even tenure. Nothing much ever comes of the labor. How should a university be run? Who is really in charge, holding the power? The proper answer is, of course, nobody. I know of one or two colleges and universities that have actually been tightly administered, managed rather like large businesses, controlled in every detail by a president and his immediately surrounding bureaucrats, but these were not really very good colleges or universities to begin with, and they were managed this way because they were on the verge of running out of money. In normal times, with institutions that are relatively stable in their endowments and incomes, nobody is really in charge.
