by Lewis Thomas
At another level, less profound but perhaps easier to get at, is the problem of resistance to cancer. It is remarkable that heavy cigarette smoking leads to lung cancer in as high as 10 percent of lifetime smokers, but even more remarkable that 90 percent do not develop cancer. The overall incidence of cancer of all types, in all societies, whatever the difference in environmental hazards, is estimated to be fixed at around 25 percent, suggesting that three quarters of us may be in possession of mechanisms for successfully resisting cancer throughout our lives. There are some cancer patients who seem to be cancer prone; multiple cancers affecting different organs are by no means rare, and the statistical probability that a patient who has been surgically cured of one type of cancer will subsequently develop another type in another tissue is significantly higher than for the population at large. Children born with defective immunological systems are much more likely to develop lymphomas than normal children.
It may be that there is an immune reaction to the appearance of the first cancer cells, which is mobilized as soon as the alien nature of these cells is recognized. Such a mechanism, if it exists in human cancer, might be the one that protects the 75 percent of us who will never develop the disease. Perhaps all of us are experiencing, from one carcinogenic environmental influence or another, the emergence of single cancer cells and a few of their progeny from time to time, in one tissue or another, and eliminating them promptly when they are perceived as foreign by our lymphocytes. If the recognition comes too late, or not at all, cancer develops—and that accounts for the susceptible 25 percent of us. I proposed this notion twenty-five years ago, and it was elaborated later by Burnet under the term “immunosurveillance.” It remains an unproven theory, but I retain high hopes for it as well as a certain affection, since it was one of my few excursions into theoretical biology.
In recent years, the theory has received indirect but solid support from an unrelated quarter in medicine. A substantial number of people around the world have by this time received kidney or heart transplants, surviving successfully under prolonged treatment with drugs which suppress the cellular immunity system which would otherwise cause rejection of the grafts. Among these patients, approximately 10 percent have developed cancer within the first year after transplantation. Of the renal transplant patients who have survived for ten years, the cancer incidence is nearly 50 percent. The cancers have been of all varieties, but with a much higher percentage of lymphomas than would be expected in the age groups involved. One explanation for this phenomenon—the currently conventional one—is that the immunosuppressive drugs are themselves directly carcinogenic. The alternative explanation, which I favor, is that the emergence of these malignancies is the predictable result of the loss of “natural” immunity. The same tumors would be appearing in all the rest of us, except for our natural capacity to kill off the first cells every time.
The rare but spectacular phenomenon of spontaneous remission of cancer persists in the annals of medicine, totally inexplicable but real, a hypothetical straw to clutch in the search for a cure. From time to time patients turn up with far advanced cancer, beyond the possibility of a cure. They undergo exploratory surgery, the surgeon observes metastases throughout the peritoneal cavity and liver, and the patient is sent home to die, only to turn up again ten years later free of disease and in good health. There are now several hundred such cases in world scientific literature, and no one doubts the validity of the observations. But no one has the ghost of an idea how it happens. Some have suggested the sudden mobilization of immunological defense, others propose that an intervening infection by bacteria or viruses has done something to destroy the cancer cells, but no one knows. It is a fascinating mystery, but at the same time a solid basis for hope in the future: if several hundred patients have succeeded in doing this sort of thing, eliminating vast numbers of malignant cells on their own, the possibility that medicine can learn to accomplish the same thing at will is surely within reach of imagining.
I look for the end of cancer before this century is over. It used to be the convention for people in my position to guess fifty years out, just to be safe, but I have become much more optimistic in the last few years. Indeed, I now believe it could begin to fall in place at almost any time, starting next year or even next week, depending on the intensity, quality, and luck of basic research. The world of medicine is becoming filled with the prospect of surprises, and this will surely be one of them.
When it does come about, I of course hope it happens first at Memorial Sloan-Kettering. But it could happen anywhere in the world, and with the system for exchanging scientific information working as swiftly and accurately as it does these days, with the news of last week’s experiments in Pasadena or New York or Paris reaching the ears of researchers in Tokyo or New York or Melbourne almost overnight, it will be a difficult task for scientific bibliographers and historians to sort out the credits. Indeed, one of the splendid features of the scientific enterprise has always been the urgency with which the participants have insisted on displaying the results of their work as soon as it is completed. With very few exceptions (most of these involving the technology of commercial developments for the marketplace rather than the items of actual discovery) there are no kept secrets in research. The only sure reward for the investigators is the exhibition of their work for everyone else to see. The published paper, ready for public scrutiny and criticism, is the whole point of the profession and the only way of advancement for the working scientist. There are no real national boundaries or barriers: Western immunologists know, down to the finest detail, what is happening in their field in Prague; Western mathematicians know what their colleagues in Warsaw and Lublin are up to; the theoretical physicists at Columbia seem to know, in general, what is going on in their fields in Moscow.
For cancer, the credits will have to be widely distributed no matter what institution claims priority for the final, successful step. I imagine that the last decisive answer, whatever it is, will come as an astonishment to everyone, and most investigators will then wonder why someone else thought of doing precisely the right experiment before they thought of it, but it cannot possibly come as an overwhelming surprise. It will almost certainly be a piece of new information that will fit perfectly, locking itself neatly in place at the apex of the huge mass of information already accumulated, and it will depend, for the sense it will make, on the preexisting coherence of that mass.
I shall rationalize in this way if the ultimate discovery turns out not to be made at Memorial Sloan-Kettering. I shall claim, and I am even inclined to claim it now, in advance, that Memorial Hospital has already been at it for almost a century, feeding in one item after another down through the years, and the Sloan-Kettering Institute has already invested over thirty-five years of its talent and energy on the problem, building a solid part of the pyramid now waiting to be topped off by exactly the right new set of experiments.
19
OLFACTION AND THE TRACKING MOUSE
I learned a little about olfaction during my residency in neurology at the Neurological Institute in the late 1930s. The former chief of neurosurgery, Dr. Joseph Elsberg, was still working at the institute then, and his scientific obsession was the use of olfactory acuity as a physical sign in the diagnosis of brain disease. He had worked out a complex system of glass vessels with blowers connected to tubes fitted into the nostrils with which he and his assistants were able to measure, with a rough degree of quantitation, the perception of tiny amounts of juniper, camphor, cinnamon, and the like in each side of the nose. The group had established the usefulness of the procedure in the localization of certain malignant brain tumors located in the deeper regions of the frontal and temporal lobes. The trouble with the procedure was that it required extreme patience and experience, and great skill, on the part of the technicians who carried it out, and the results were of significance in such a small proportion of the patients in the hospital that it was finally given up. None of th
e younger members of the neurosurgical staff was interested enough to continue the research work after Elsberg retired.
I did some reading in the field at the time, and found the literature on olfaction obscure and sparse. Nobody seemed to know much about the matter. The olfactory receptor cells were known to be bona fide brain cells, the only proper neurones in the brain that are exposed to the outside world and act as their own receptors of information from the environment. All the others, those concerned with the senses of touch, position, taste, hearing, and vision, depend upon relays of nerve impulses coming in from highly specialized receptor cells which pick up the appropriate stimuli at the periphery and send them along to centers in the interior of the brain which are set up to make sense of the sense. The most curious and remarkable thing about the olfactory neurones is that they come and go, replicating and replacing themselves in their positions at the surface of the olfactory mucosa, high up in the back of the nose. No other brain neurones have the property of multiplying or regenerating; once in place, the neurones of the rest of the brain are there for the duration of life, and those which age and die off are not replaced. But the olfactory receptor neurones keep coming; in the mouse they have been shown to have a turnover of the population every two to three weeks. Another peculiarity of these cells is that despite their exposure to the outside, and their location in a region of the air passages which is especially rich in bacteria and viruses of all sorts, the tissues in which they reside do not become infected. It was thought at one time that the poliomyelitis virus made its way into the brain by way of the olfactory neurones, but this was later proved wrong. It is now believed that the cells are somehow protected by the antimicrobial property of the mucus which is always present as a thin layer covering the cells.
From time to time, new information about olfaction appeared in the physiology literature, and a series of international conferences dealing with the phenomenon began in the 1950s. I kept in touch with this material as best I could, as an outsider, and one day about ten years ago I ran into some references to observations made much earlier—as far back as the 1920s—on the accomplishments of tracking hounds. A great deal of solid work had been done at that time, most of it sponsored by European police departments, on the capacity of trained dogs to track the footsteps of a single human being across fields marked at the same time by the tracks of other people.
Much of this was anecdotal, based on single observations made in the course of field trials and interdepartmental competitions, but the anecdotes were abundant and consistent, building a consensus accepted all round: a well-trained hound could distinguish with accuracy an odor of some kind arising from the track of a human being, for as long as forty-eight hours after the laying of the track, and could distinguish this particular track from all other tracks laid by other human beings.
If this was indeed true, it meant that the dog was able to smell a signal coming from the track which identified each human being as an individual self. But another elaborate and precise biological system was already known to exist for the same purpose: immunological markers that signal selfness are present at the surface of all cells in the body; the sensing of these chemical molecules is responsible for the fact that skin grafts are rejected with surgical precision when the grafts come from someone else, unless the foreign skin is taken from one identical twin and sewn into the skin of the other. This is believed to be a universal phenomenon: except for the exchange of tissues between identical twins, the skin of no one of the 4 billion human beings on the planet can be grafted successfully to any other. Grafting can be done these days with kidneys, even hearts, but only with the aid of drugs that incapacitate the lymphocytes responsible for immunologic rejection of non-self tissues.
It seemed to me strange that two different systems would have arisen for the same function in evolution, separately and unrelated to each other, and I began to speculate that they might indeed have evolved from a single ancestral system employed, early on in evolution, for enabling the first primitive organisms to make distinctions between their own cell surfaces and those of others. Such mechanisms are known to exist abundantly in the most ancient of metazoan creatures, sponges and corals for instance. Moscona showed some years ago that when the separated cells of two species of sponge are mixed together and rotated in a saline suspension, the two kinds of cells will reaggregate in clusters, each of which is made up exclusively of one or the other species. The cells can evidently recognize their own kind as self, and can at the same time avoid sticking to the non-self cells. Jacques Theodor placed together two pieces of soft coral of the same species, but from different colonies on the reef, and observed that, after first fusing to form a single frond of coral, the two bits would then separate from each other, precisely along the original line of apposition, with death of all the cells in the immediate vicinity of that line. Recently, Hildemann and his associates have observed the same sort of graft rejection in sponges: two sponges from the same colony will fuse together permanently, but when the sponges are of the same species but from different colonies, they will reject each other ten or twelve days after fusing. Moreover, the sponges seem to have a specific memory of the event; when the separated explants are again placed together, but with different surfaces confronting each other, the rejection reaction occurs in accelerated fashion, two to three days later. The phenomenon is remarkably like graft rejection in the mouse: the first skin graft from a foreign mouse is rejected in eight to ten days, but a second graft of the same tissue is rejected in three or four days.
In mice, the reaction of graft rejection is primarily a function of a particular class of lymphocytes, the so-called T-lymphocytes (so designated because of their origin in the thymus gland). The reaction is controlled by a special set of genes, called the H-2 locus, always situated together on a single chromosome. In man, the corresponding gene locus, governing the self–non-self distinction and the rejection of tissue grafts, is known as the HLA locus.
Several years ago, when invited to deliver an address before an Immunology Congress on possible future lines of immunologic research, I discussed the problem of self-marking and expressed the view that it would be remarkably unparsimonious of nature to set up two such elaborate and complex systems for individual self-marking—costly in terms of energy, one involving the immunologic markers of histocompatibility and the other using olfaction—and to have these two mechanisms evolving without being closely related to each other. I made at that time what I thought was a mild biological joke, predicting that the same set of genes would be found responsible for both systems of labeling, and that someday “man’s best friend would be used for sniffing out histocompatible donors.”
A while ago I was discussing this with Dr. Edward Boyse, whose research laboratory in Sloan-Kettering makes daily use of an extensive collection of meticulously inbred and sharply defined lines of mice. His wife, Jeanette Boyse, has the immediate responsibility for overseeing the breeding of various lines of congenic mice, in which the sole genetic difference between two lines lies in the H-2 locus on chromosome 17, the locus governing graft rejection and coding out the major histocompatibility complex (the MHC) of tissue antigens. The mice are contained in transparent boxes so that their mating behavior can be kept under close and constant observation. Mrs. Boyse had just noticed that the males of certain lines displayed a preference for mating with females of the opposite line possessing different H-2 genes. The possibility was raised that perhaps the male could smell the difference, and since these were two lines of genetically identical animals, except for the H-2 difference, it was obvious that the capacity of a male to smell such a difference would have to involve an olfactory distinction between self (in strict terms of individual self) and non-self.
It did not take long for the Boyses, together with two young postdoctoral fellows at Sloan-Kettering, Drs. Yamazaki and Yamaguchi, to establish with satisfactory statistical significance that the phenomenon of mating preference between H-
2 congenic mice was real and consistent. We then moved on to a simpler system for getting at the same problem, which involved, at the outset, training a tracking mouse.
In brief, the technique was based on the classical Y-maze, with two different odors coming down the arms of the Y, one from the tracking mouse’s own line, the other from the congenic line differing from himself only at the H-2 locus. The reward for selecting the correct arm was a drop of water, and the tracker was urged to seek the drop by being deprived of water for the preceding twenty-four hours. Training was begun by teaching the mouse to distinguish between the odor of cinnamon and juniper; then, when he’d got the idea, he was trained to discriminate between the smell of his own and a totally different breed of mouse, and finally to detect the odor of the congenic line, in this case the difference between B-6, his own line, and B-6 H-2k, the other strain.
The experiments worked, and have continued to work, with a surprising degree of consistency and reproducibility. In all, eight smart tracking mice have been taught to smell H-2 during the past two years. Each experimental trial involves twenty-four runs toward the target, which is changed from one arm to the other at random, and the correct or incorrect choices are recorded by a third party who is himself unaware of the correctness of the choice. With a very high degree of statistical significance, each tracker has learned to distinguish between his own smell and the congenic smell when the odor box leading to the arm of the Y-maze contains mice of the proper genetic line. The odor is not detectable in homogenates of various mouse tissues, including spleen, liver, kidney, lung, or brain, nor can it be detected when mouse embryos are in the box. However, it is readily detected, with an accuracy even greater than when whole live mice are in the odor box, in samples of urine. The tracker can detect the odor of congenic urine when the urine is contained in a petri dish in the odor box, and the smell is still perceived when the urine has been diluted 1–40. The odorant is surprisingly stable, withstanding boiling for one hour. It is a small enough molecule to pass through a dialysis sac.