The Youngest Science

by Lewis Thomas

  We have since learned that the same odorant can be detected in the urine of F-2 segregants derived from crosses between the two congenic lines, effectively ruling out smells derived from parental environment or family litter boxes.

  It would be very nice to know which cells in the body are responsible for manufacturing the self-identifying odorant that ends up in the urine. The leading candidates for this role, in my view, are the lymphocytes themselves, because of the central role they play in mediating the homograft-rejection mechanism. An experiment still in progress at the Monell Institute has already produced suggestive evidence in favor of this idea. Yamazaki has transformed a mouse of one congenic line (B-6) into one of the other line (B-6 H-2k), by irradiating B-6 mice to destroy all of their bone marrow cells and then transfusing them with lymphoid cells from the H-2k line to repopulate the now-empty bone marrow. Thus, what used to be a pure-line B mouse was turned into a mouse with the K marker on its lymphocytes. Urine from such transformed mice was then tested in the Y-maze to see what it smelled like to the trained tracker. It was recognized as K urine, indicating that the odorant is secreted into the urine (and probably concentrated there) as the result of activity on the part of bone marrow cells—most likely the lymphocytes in the bone marrow.

  The same odor is responsible for the phenomenon of pregnancy blocking, the so-called Bruce effect. This is the peculiar reaction that occurs when a newly impregnated mouse is placed in contact with a strange male: the pregnancy is promptly terminated and the female goes into estrus. She does not do so, of course, when the contact is with the original stud responsible for her pregnancy.

  Using congenic lines of mice, differing only at H-2, Yamazaki and the group have found that replacing the original stud with a different male of the same line does not cause the Bruce effect, but when the new male is of the line with a different H-2 locus, the pregnancy stops and estrus resumes in the majority of females. The actual presence of the H-2 foreign male is not needed for this effect; the same results occur when the pregnant female is in the immediate vicinity of a sample of urine from the appropriate line.

  The Bruce effect is not induced by exposure to females of the congenic line, or by urine from such females. Thus the Bruce effect must be caused by the perception by the pregnant female of two distinct and separate signals, one indicating maleness, the other announcing the presence of a male with a different H-2 locus.

  I know of no satisfactory explanation for the Bruce effect, not anyway in teleological terms. Perhaps it represents a built-in response which tends to enhance heterozygosity and, to some extent, to impair close inbreeding. Or perhaps—and this is the teleology I prefer—the mere presence nearby of a strange male, differing in the odor of his H-2 from the original stud, signifies the departure of the father and the loss of protection to be expected from him for the forthcoming litter, and therefore it is time for the female to give it up and start over again. Our experiments have told us nothing about this, only that the smell of male strangeness is coded by the same string of genes that code for immunological strangeness.

  Last year, Dr. Boyse and I had the opportunity of observing tracking dogs at work, first at the dog-training station of the Baltimore police department, then later at the Scotland Yard station just south of London. We saw enough to convince us that the specific and selective tracking of a man was a genuine and reproducible phenomenon, and that it ought to be entirely feasible to set up experiments to settle the question of whether identical twins leave identical tracks and even—although here I can envisage some formidably difficult technicalities—trying to correlate tracking accuracy with human HLA types. Needless to say, we have not set out on either of these lines, but some of the things we have already observed are perhaps of anecdotal interest even if not of scientific value. One curious thing we hadn’t known: when a hound sets off on the track of a designated man, he does so not with his nose close to the ground, as in the movies, but rather tossing his head high, from side to side, as he goes. When the track turns at a sharp angle he overruns it, of course, but when he comes back to regain it he does so by sniffing the air well above the ground surface, getting clues not from the ground itself, or from footprints, but from something rising away from the ground.

  In the Scotland Yard trials, we brought along several squares of gauze that had been placed in the bedding of various cages containing the two congenic groups of mice, differing from each other by only the genes for immunologic self-marking, and asked the trainer to see if his dog could learn to distinguish between the two. The squares were laid out at random, at intervals over a long slab of grass, the dog was given the scent of the one to be selected, and he trotted rapidly along with his head held several inches above the gauze squares until he reached the correct one, which he picked up neatly in his teeth and brought back to his master as though carrying the evening paper. The whole operation seemed so effortless as to be nearly automatic and, from the dog’s point of view, the easiest of things. If we humans possess pheromones that label each of us as a person, I am glad to say that we cannot, as a rule anyway, smell them, social life being complicated enough as it is, but it would not surprise me at all if a Scotland Yard hound could do so, and could readily pick up the fragrance of any one urine sample and tell it from all the rest.

  But even with the technical limitations of the tracking mouse and the Y-maze, it ought to become possible to learn something now about the chemical nature of the H-2 coded olfactant in mouse urine. Indeed, Drs. Yamazaki and Yamaguchi have recently transferred their laboratories to the Monell Institute in Philadelphia, where the chemistry of odorants is a high-technology specialty, for this purpose. There will surely be some interesting questions. What sort of heat-stable substance can it be, possessing enough variability in its structure to provide unique self-markers for the numberless individual mice, or, for that matter, 4 billion human beings? I imagine that it will turn out to be a set of chemicals, probably of the same class but with structural variations, arranged in infinite numbers of possible medleys, possibly very small changes in the intensity of one or another member of the group, and with each individual’s odor sounding a unique chord.

  Perhaps some similar arrangement of groups of molecular signals will account for the apparently infinite variability of cell markers in the immunologic system. It is conceivable that the tissue antigens are similar sets of different signals, displayed in varying concentrations to achieve uniqueness. It is not beyond imagining that the actual molecular configurations that fire off the olfactory receptor cells might turn out to be the same, or closely related to, the ones that, in the end, fire off a T-lymphocyte. And, to carry the matter as far as it can be stretched, it is even imaginable that some signal arrangement of this sort is at work in the homing of embryonic cells, the self-preservation of sponges, and the preservation of internal privacy within an amoeba. If so, it adds something more to the complexity of life for the single cell. It is not a simple life to be a single cell, although I have no right to say so, having been a single cell so long ago myself that I have no memory at all of that stage of my life.

  20

  ILLNESS

  One of the hard things to learn in medicine, even harder to teach, is what it feels like to be a patient. In the old days, when serious illness was a more commonplace experience, shared round by everyone, the doctor had usually been through at least a few personal episodes on his own and had a pretty good idea of what it was like for his patient. A good many of the specialists in pulmonary disease who were brought up in the early years of this century had first acquired their interest in the field from having had tuberculosis themselves. Some of the leading figures in rehabilitation medicine had been crippled by poliomyelitis. And all physicians of those generations knew about pneumonia and typhoid at first hand, or at least once removed, in themselves or their immediate families.

  It is very different today. The killing or near-killing illnesses are largely reserved for
one’s advancing years. No one goes through the six or eight perilous weeks of typhoid anymore, coming within sight of dying every day, getting through at the end with a stronger character perhaps, certainly with a different way of looking at life. The high technologies which are turned on to cope with serious disease—the electronic monitors in intensive care units, the chemotherapy drugs for cancer, the tour de force accomplishments of contemporary surgery, and the mobilization of increasingly complex procedures for diagnosis in medicine—are matters to be mastered only from lecture notes and books, and then by actual practice on patients, but very few doctors have more than an inkling of what it is actually like to go through such experiences. Even the childhood contagions are mostly gone, thanks to vaccines for measles, whooping cough, chicken pox, and the like, thanks especially to the easy control of streptococcal infections. Today’s young doctors do not know what it is to have an earache, much less what it means to have an eardrum punctured.

  The nearest thing to a personal education in illness is the grippe. It is almost all we have left in the way of on-the-job training, and I hope that somehow it can be spared as we proceed to eliminate so many other human diseases. Indeed, I would favor hanging on to grippe, and its cousin the common cold, for as long as possible. A case could be made, I think, for viewing the various viruses involved in these minor but impressive illnesses as a set of endangered species, essentially good for the human environment, something like snail darters.

  Most people afflicted with grippe complain about it, and that is one of its virtues. It is a good thing for people to have, from time to time, something real to complain about, a genuine demon. It is also a good thing to be laid up once in a while, compelled by nature to stop doing whatever else and to take to bed. It is an especially good thing to have a fever and the malaise that goes along with fever, when you know that it will be gone in three or four days but meanwhile entitles you to all the privileges of the sick: bed rest, ice water on the bed table, aspirin, maybe an ice bag on the head or behind the neck, and the attentions of one’s solicitous family. Sympathy: how many other opportunities turn up in a lifetime to engage the sympathy and concern of others for something that is not your fault and will surely be gone in a few days? Preserve the grippe, I say, and find some way to insert it into the practical curriculum of all medical students. Twice a year, say, the lecture hall in molecular biochemistry should be exposed to a silent aerosol of adenovirus, so that the whole class comes down at once. Schedules being what they are in medical school, this will assure that a good many students will be obliged to stay on their feet, working through the next days and nights with their muscle pains and fever, and learning what it is like not to be cared for. Good for them, and in a minor way good for their future as doctors.

  The real problem is the shock of severe, dangerous illness, its unexpectedness and surprise. Most of us, patients and doctors alike, can ride almost all the way through life with no experience of real peril, and when it does come, it seems an outrage, a piece of unfairness. We are not used to disease as we used to be, and we are not at all used to being incorporated into a high technology.

  I have learned something about this, but only recently, too late to do much for my skill at the bedside. On several occasions, starting around age sixty-four, I have had a close look from the bed itself at medicine and surgery and, as I shall relate, an even closer look at myself. On balance, I have very much liked what I have seen, but only in retrospect, once out of bed and home free. While there, I discovered that being a patient is hard work.

  It is often said that people who have been precariously ill, especially those who have gone through surgical operations, love to talk about their trials and will do so at length to anyone ready to listen. I rather doubt this. Being ill is a peculiarly private experience, and most of the people I know who have gone through something serious tend to be reserved about it, changing the subject when it comes up. But here I am, about to talk about my times on the line and the things I learned. I only do so, I must say in advance, out of professional interest.

  The first, and most surprising of all, was an obscure kind of pneumonia, chills, fever, prostration, and all, occurring suddenly on a Tuesday afternoon. I took to bed at home in good cheer, anticipating several days of warm soup, cold drinks, fluffed-up pillows, and ample family ministrations. But a week went by and I kept on with the chills and fever, so my wife called the doctor, a friend of mine and a real, house-calling doctor. He did the usual things, including taking samples of blood, murmured something about a virus “going around,” and predicted that the fever would be gone in another day or two. But the next day I was in a hospital bed having more blood tests, being examined by platoons of interns and residents, and in and out of the X-ray department having pictures taken of all sites including bones. The laboratory tests had revealed a hemoglobin level of just under 8 grams percent, half the normal value, and it had become an urgent matter to discover where the blood had gone, or was going.

  Within the next few days the pneumonia vanished, along with the chills and fever, and I had become a new sort of diagnostic problem.

  To be worked up for anemia of unknown origin is strenuous exercise. The likeliest cause was blood loss, and the likeliest source was the intestinal tract—what is known, ominously, as silent bleeding. I received two transfusions, and then plunged headlong into technology. A bone marrow biopsy was, as I recall, the first piece of work, done neatly and quickly on a pelvic bone with rapid-fire explanations by the hematologist as he went along, telling me what I would feel and when it would hurt, but despite his reassurances I could not avoid the strong sense that having one’s bone marrow sucked into a syringe was an unnatural act, no way for a human being to be treated. It did not in fact hurt much, but the small crunching of bone by the trocar followed by the peculiar and unfamiliar pain in the marrow itself were strange sensations, not at all nice.

  I have performed bone marrow biopsies myself, long ago as an intern and from time to time since, and have always regarded the procedure as a minor one, almost painless, but it had never crossed my mind that it was, painless or not, so fundamentally unpleasant.

  The rest of the workup was easy going and at times engrossing. The walls of my stomach and upper intestinal tract were marvelously revealed by a barium meal, and those of my bowel by a similar enema, and all was well. But I continued to bleed, somewhere in that long channel, and more transfusions were needed.

  It is not an easy task for doctors to look after doctors, and especially difficult when the doctor-patient is a colleague and close friend. It requires walking a fine line, making sure not to offend professional pride by talking down to the doctor-patient, but also making sure that the patient does what he is told to do. I was treated with great tact and firmness. The colleagues and friends who had me as a responsibility remained my good friends, but there was never a question as to my status: I was a patient and they expected me to behave like one. I was not to try making decisions about my own diagnosis and treatment. I was not allowed to go home for a few days, which I wanted very much to do at several times during what turned out to be a long period of hospitalization; it was explained very gently that the source of bleeding was still unknown and I might have a more massive hemorrhage at any time, rather less gently that if it happened I might suffer a lot of brain damage and I’d better not be doing that at home.

  With negative X rays, my intestinal tract needed a different kind of look. On the possibility that I might have a polyp somewhere, bleeding freely but too small to show up by X ray, I was wheeled off to the endoscopy service for examination by the colonoscope, an incredibly long and flexible quartz fiberoptic tube through which all parts of the large intestine can be viewed under direct illumination by light sent in from outside. As a nice gesture of professional courtesy, the doctor stopped at frequent intervals during this procedure and passed the viewing end of the instrument over my shoulder and in front of my left eye. “Ca
re to take a look?” he asked. I had never looked through this wonderful instrument before, although I had seen many photographs of the views to be had. It would have been interesting in any case, I suppose, but since it was the deep interior of my own intestine that I was looking at, I became totally absorbed. “What’s that?” I cried, as something red moved into view. He took a look and said, “That’s just you. Normal mucosa.”

  A few days after this fascinating but negative excursion, I had another episode of bleeding, my hemoglobin dropped to a disturbing level, more transfusions were given, and it was decided that I would probably need surgery in order to remove the part that was presumably bleeding. But without knowing the exact source, this could mean taking out a lot of intestine and, even then, missing it. The gastroenterologist who had me in charge, Dr. Paul Sherlock, knew of one obscure possibility not yet excluded, one that I had never heard about—a condition produced by an abnormal connection between an artery and vein in the intestinal wall—which had recently been reported as a cause of intestinal hemorrhage.

  This was not, as it seemed to me at the time, a guess in the dark. The X rays and colonoscope had ruled out cancer of the colon (which is what I was pretty sure I had, at the outset), and diverticulosis (little cracks in the intestinal wall), and polyps had been excluded as well. The new syndrome of arteriovenous anomaly was about all that was left.

  Finding out required close collaboration between the gastroenterologists and radiologists. A catheter was inserted in the femoral artery, high up in the right leg, and pushed up into the aorta until its tip reached the level of the main arteries branching off to supply the large intestine. At this point, an opaque dye was injected, to fill all those arteries. Just before pressing the syringe, Dr. Robin Watson, the X-ray chief, warned me that I would feel a sense of heat, not to worry. It was a brand-new sensory impression, perhaps never experienced except by patients undergoing this kind of arteriography: for about thirty seconds I felt as if the lower half of my body had suddenly caught fire, then the feeling was gone. Meanwhile, movies were being taken of the entire vascular bed reached by the dye, and the diagnosis was solidly confirmed. Dr. Watson came into the room a few minutes later with sample pictures displaying the lesion. “Care to take a look?” he asked. I was enchanted: there, in just one spot somewhere on the right side of my colon, was a spilled blur of dye, and the issue was settled. It struck me as a masterpiece of technological precision, also as a picture with a certain aesthetic quality, nice to look at. I could hear in the distance the voices of other doctors, quietly celebratory as doctors are when a difficult diagnosis is finally nailed down.