Nature can be explored on many levels; none is more or less profound, none is more or less correct, but they are different. Which one you choose depends upon inclination, talent, accident, but most of all, unfortunately, upon fashion.
Erwin Chargaff, "Preface to a Grammar of Biology"
The science of immunology has its roots in attempts to understand how animals resist the invasion of bacteria. The study of man's resistance to infection appeared to become obsolete with the discovery of the sulfa drugs and antibiotics. What difference did antibodies make, if you could kill disease germs with antibiotics? It didn't take long before we found out that the killing of germs was only one part of the problem of resistance to disease. Furthermore, there are no antibiotics against viruses.
The discovery of human blood groups and the feasibility of transfusion opened up another field of immunology: the immunology of transplantation. Recently, there has been an increased interest in transplantation research. The technical (surgical) difficulties in transplanting organs have been pretty well surmounted, but most heart transplant patients have died, because no one has found a way of preventing the body from "rejecting" the "foreign" heart. At the present time, immunologic problems are the concern of some of the best minds in research. They are attacking the problem of how the body knows friend from enemy (self-recognition), the chemical structure of antibodies, the genetics of transplantation, and which cells of the body do what and how (cellular immunology). Immunology has also fallen into the hands of the therapists.
One of the exciting problems in immunology is the problem of "self-recognition." We know that adult animals will "attack" bacteria, egg albumin, and all sorts of foreign substances that get to the inside of the animal. It does not attack Its own cells under ordinary conditions. We know that cancer cells are also an animal's own cells, but there are some who claim that they are different enough to be recognized as foreign. There is some evidence for this: for one thing, certain tumors show microscopic evidence of an immune reaction around the tumors, and animals sometimes have antibodies against their own tumor cells. Unfortunately, this difference is usually not great enough to destroy the tumor. If it were, the tumor would not be there in the first place. If a tumor can outwit chemicals, radiation, and a host of other regulatory mechanisms, It can also outwit the immune system, and it does.
It has been known for a long time that an animal does react in some way against its tumors. In the last ten years, cancer immunologists have discovered that tumors induced by viruses have characteristics that are attributable to the virus that caused the tumor. A virus called polyoma will induce all sorts of tumors if it is injected into newborn animals. If the virus is injected into adult animals, the animal responds by producing antibodies against the virus in the same way as it does to any disease agent; and tumors are not produced. If two sets of animals of the same age and the same strain are injected with a tumor that has been produced by polyoma, it takes a hundred times as many tumor cells to get the tumor to "take" (to establish in the animals, and start to grow) in an animal that has antipolyoma antibodies than in one that is not immune. Antibodies against polyoma virus, which have been tagged with a fluorescent dye so that they can be seen, will attach themselves to the surface of the cells of any tumor that has been produced by polyoma virus.
Ten years ago, before cancer immunology became popular, an experimental therapist injected some of his patientŐs cancer Into animals and produced antibodies against the cancer. The antibodies were concentrated and were Injected into the patientŐs cancer. Sure enough, they attacked it and destroyed parts of it; but the patient died. Antibodies can be used in much the same way as any other lethal chemical or x-ray or knife. The same problems exist with the use of antibodies that exist with the use of other agents, and most just donŐt work very well. One of the reasons that they donŐt work is that the tumor cells themselves have already escaped from whatever immunologic mechanisms the animal had, and the tumor cells also have the adaptive capacity to outwit most challenges. It might someday be possible to use an animal's own immune mechanism to fight a tumor, but it has not been effectively used to date in man.
With the exception of identical twins, every individual mouse or individual human is different from its fellows. These differences are genetically determined by a number of genes which result in a large number of possible genetic combinations. In the early days of cancer research, rare tumors were discovered which could be transplanted from one mouse to another or one rabbit to another; that is, they were able to cross the immune barriers between Individuals. The differences between the tumor and the animal in which it was implanted still existed, but the tumor was able to kill the host before it could mount adequate immunological defenses which might, In turn, kill the tumor. When such tumors were treated by almost any means (surgery, chemicals, x-ray), the animal was cured of the tumor. Scientists were curing cancer right and left; and by using this type of artificial system they are still "curing cancer." By the 1930s, enough strains of "inbred" mice had been produced to allow the transplantation of cancers to have some real meaning. Inbred mice are produced by mating a single brother-sister pair, and doing the same thing with their offspring. when this has been done for many generations, the result is a "strain" of mice in which all animals have the same genetic makeup. With an inbred strain of animals, It is possible to transplant skin, tumors, tissues, and organs from one animal to another within the strain, without engendering any immunologic reaction at all. Tumors have been kept alive for long periods of time by transplanting them from one mouse to another within the same strain. In these systems, the immunologic differences between the tumor and the animal are so weak that they can only be detected by very delicate quantitative technics and the "rejection" of a tumor transplant will occur only if a very small amount of tumor is inoculated.
The problems that are being tackled by immunologists may have a profound bearing on our understanding of cancer, disease, and graft rejection. Some of these are the following:
I. How does a cell recognize a substance, or cell, or microorganism as foreign? In other words, how can an animal distinguish friend from enemy?
2. What is the relationship of the chemistry of antibody to the chemistry of the substance (antigen) that induced the formation of the antibody?
3. There are a number of different types of cells involved in the immune reaction: which cell does what, and how?
In 1964, Barbara Jacobs, at the American Medical Center in Denver, was attempting to grow some transplantable mouse tumors In organ culture (this is a technique whereby a small piece of tissue can be maintained in a dish in as close to a natural state as is technically possible). In order to test whether her organ cultures were still alive, she implanted the tumor cultures into mice of the same strain that the tumor came from. If her cultures were still alive, they would grow in the mice. A new technician implanted the cultures into mice of the wrong strain. Ordinarily, when such a mistake is made, the mice are discarded because, as every biologist knows, the transplants will be rejected and the tissue destroyed. Dr. Jacobs kept the animals. Much to her surprise, the tumors were not destroyed, but grew. Not only did they grow In a foreign strain, but when they were transplanted to more mice of the same foreign strain, they continued to grow. Something had happened to the tumors that kept them from being rejected. Another mistake? Maybe the tumors were not what they were supposed to be. No, because when these tumors were transplanted back into the strain from which they had originated, they also grew. After the tumor had been grown in its original strain it relearned the rules of transplantation and could not be successfully transplanted into a foreign strain. Apparently the tumor had, in some unknown way, changed in organ culture so that it was able to violate the laws of transplantation. In the past nine years, a large number of experiments were performed which confirmed the original finding that tissues which are kept in organ culture change in some way so that they are not rejected by a foreign host. This may well be one of the most exciting discoveries in transplantation in our time; and it is a result of "cancer research." It might conceivably lead to our being able to transplant tissues and organs from one individual to another without their being rejected.
It is interesting that, to date, cancers have contributed more to our understanding of immunology than immunology has contributed to our understanding of cancer. Almost everything that is known about the chemistry of the antibody molecule has been obtained by studying the massive amounts of antibody that are produced by tumors of antibody forming cells (plasma cells) in man and the mouse. This is likely to also be true in the future, when tumors of other cells of the defense system are studied in detail. It would be interesting if cancer cells turned out to be the means by which scientists will obtain the knowledge that will allow them to transplant various organs across the barriers of individuality.