The Patchwork Mouse
“Can the leopard change his spots?” the prophet asked (Jeremiah, 13: 23), clearly not expecting to be told he can. Nor, indeed, can mice, except under the rather discreditable circumstances now to be outlined.
It is a well-attested truth of observation that except under special and unusual circumstances skin from one mouse or human being will not form a permanent graft after transplantation to another mouse or another human being; for although such a graft heals into place it soon becomes inflamed and ulcerated, and eventually dries up and sloughs off. The exceptional circumstances are: in human beings, when donor and recipient are identical twins, and in mice when prolonged inbreeding (e.g., upward of twenty successive generations of brother/sister mating) has made the mice so closely similar to each other genetically that they almost could be identical twins.
This being so; great surprise was caused in the world of transplantation when Dr. William Summerlin, a member of the largest and in many ways the most important cancer research center in the world, the Sloan-Kettering Institute in New York, with the backing of his chief, Dr. Robert A. Good, made known in 1973 his surprising claim that a comparatively simple procedure—“tissue-culture”—could make a skin graft or a corneal graft from a member of the same or even of a different species acceptable to an organism that would otherwise have rejected it. This claim was specially important because grafting skin from one human being to another has never entered clinical practice, in spite of encouraging successes with the transplantation of kidneys, livers, and sometimes even hearts. Either skin is specially well able to excite the immunological reaction that leads to its own rejection, or it is specially vulnerable to it. This inability to graft new skin from one person to another is the greatest current shortcoming of the surgery of replacement and repair, because the replacement of skin is the only adequate treatment of extensive burns or excoriating wounds.
Summerlin’s treatment, the technical details of which, in spite of exhortation from his director, he seemed suspiciously reluctant to impart to his colleagues, amounted in principle to very little more than the incubation of the intended graft in a suitable nutrient medium outside the body for a matter of days or weeks. This seemed an astonishingly simple solution of a problem no one else had solved, although many of us had been trying since about 1940.
Unfortunately, experienced biologists in other laboratories, and eventually workers in the same institute, were unable to confirm Summerlin’s findings, so that Summerlin eventually had recourse to faking his results to convince his now uneasy chief. He touched up his grafts with a felt pen, so simulating dark skin grafts on white mice. He also claimed that operations had been done which had not been done. The formal end of the story came in 1974 when Dr. John L. Ninnemann and Dr. Good published a paper that in effect demolished the whole story.
This was all a nine days’ wonder in the world of immunology, but the nine days are now up and this is therefore a good moment, on the basis of Hixson’s very readable and, so far as I can tell, very accurate account of the whole story, to stand back and see what lessons can be learned from the whole episode. This is also Hixson’s ambition, for he says at the outset: “I hope that by the time the reader has reached the end of the book, he or she will have enough information to form an opinion about what is good and what is not so good in our current system of medical research as it pertains to cancer.” “If the reader disagrees with the author,” he goes on bravely, “why then, so much the better.”
Summerlin’s sin is not now in doubt; but it is still worth considering precisely why his action was considered so heinous by all his fellow scientists. The reason is this: scientists try to make sense of the world by devising hypotheses, i.e., draft explanations of what the world is like; they then examine these explanations as critically as they know how to, with the result that either they gain confidence in their beliefs or they modify or abandon them.
In the ordinary course of events scientists very often guess wrong, take a wrong view, or devise hypotheses that later turn out to be untenable. This is an ordinary part of human fallibility and calls for no special comment. Nor does it necessarily impede the growth of science because where they themselves guess wrong, others may yet guess right. But they won’t guess right if the factual evidence that led to formulating the hypothesis and testing its correspondence with reality is not literally true. For this reason, any kind of falsification or fiddling with professedly factual results is rightly regarded as an unforgivable professional crime.
In trying unsuccessfully to get the same results as Summerlin, my colleagues and I wasted a lot of time that might have been much more fruitfully employed. Our failure—and the failure of others—to repeat his results was not in itself irremediably damaging, for this, too, is an ordinary part of scientific life. After Rupert Billingham, Leslie Brent, and I published experiments showing quite clearly that the problem of how to overcome the incompatibility barrier between unrelated individuals was indeed soluble, several people tried to repeat our work and failed. There were, however, always good reasons why they did so; either they had introduced into our techniques little “improvements” of their own, or they were too clumsy or something. These failures did not disturb us in the very least: we knew we were right—and we were—so we did our best to tell those who were struggling with our techniques how best to carry them out. As Hixson makes plain, Summerlin was suspiciously at fault, for he simply would not divulge his methods. Indeed, matters reached such a point that Leslie Brent, one of the world’s foremost experts on transplantation, was driven in desperation to send a whole file of his correspondence with Summerlin to Dr. Good, an action unwillingly taken which led to Summerlin’s being severely reprimanded.
A particularly exasperating characteristic of the whole episode was that Summerlin’s claim could easily have been true and for reasons which Dr. Good described as “trivial.” They would have been trivial only because they did not point to any scientifically exciting phenomenon such as change of genetically programmed characteristics in the graft, for example its makeup of immunity-provoking substances. But from the point of view of clinical usefulness it obviously didn’t matter whether the explanation was profound or trivial. So many of us—even those who like myself shared Good’s view that the reasons for the grafts’ anomalous “take” were trivial—persevered in trying to repeat Summerlin’s work.
I am desperately sorry that Summerlin’s work turned out to be mistaken because its failure means that we are still without means of repairing the skin surface except by piecemeal patching with little fragments of the patient’s own skin—a process that may take weeks or even months during which the patient steadily loses body fluids and is specially vulnerable to infection.
The reader may well want to know what the very distinguished members of the Board of Scientific Consultants of the Sloan-Kettering Institute were up to all this time. My name appears repeatedly in Hixson’s book, partly as an expert on transplantation and partly as a member of the board. I cut a better figure in the pages of Hixson’s book than I did in real life—something for which I bear Hixson no ill will. My reason for saying so is that at several critical points I found myself lacking in moral courage.
Summerlin once demonstrated to our assembled board a rabbit which, he said, had received from a human being a “limbus to limbus” corneal graft—a graft which had been made compatible by his process of culturing. “Limbus to limbus” means extending over the whole dome of the cornea to the extreme rim in which the blood vessels run. Through a perfectly transparent eye this rabbit looked at the board with the candid and unwavering gaze of which only a rabbit with an absolutely clear conscience is capable.
I could not believe that this rabbit had received a graft of any kind, not so much because of the perfect transparency of the cornea as because the pattern of blood vessels in the ring around the cornea was in no way disturbed. Nevertheless, I simply lacked the moral courage to say at the time that I thought we were the victims of a hoax or confidence trick. It is easy in theory to say these things, but in practice very senior scientists do not like trampling on their juniors in public. Besides, it was still possible that for some reason, “trivial” or otherwise, the story was true. However we made no secret of our inability to repeat some of Summerlin’s experiments, so far as we were able on the basis of the very inadequate information we had.
On the one occasion when I visited Summerlin in his laboratory with his immediate coworkers and technical helpers, and asked a number of hostile questions, I noticed with some surprise that our duologue was causing the others quite a lot of amusement. In retrospect, and after learning from Hixson the part Summerlin’s technicians and immediate coworkers played in showing up the counterfeit, I can now see that they were sardonically amused at Summerlin’s being interrogated in this way. But the equally plausible hypothesis I formed at the time was that, being only human, they were in reality amused at the obvious discomfiture of an eminent visiting scientist who, from the nature of his position on the board, was “one of them” rather than “one of us.” But for whatever reason, I did not forthrightly express any grave doubts about the probity of the whole enterprise.
In cases such as Summerlin’s it is the usual thing to go over the culprit’s career to find premonitions in his early life of how he behaved later. Hixson has done a good job here, reporting upon an unproved charge that Summerlin cheated in exams during his sophomore year at Emory University School of Medicine. It is, of course, possible that Summerlin was what is known in the world of criminology as a “bad apple,” but this diagnosis lacks psychological depth.
I believe that there is a fairly simple explanation of Summerlin’s egregious folly. It is this: in his early experiments Summerlin did actually obtain, with mice, the results that later aroused so many misgivings. Mice can sometimes get muddled up even in the best regulated laboratories, and it is just conceivable that in his earliest experiments the recipient mice which Summerlin believed to be genuinely incompatible with their donors were in reality hybrids between the strain of the graft donor and some other mouse.