If you think that the mouth and the intestines are simply an extension of our skin, sword swallowing doesn't seem quite so miraculous.

A very useful concept when we talk about cancer, or about animals in general, is to clarify what we mean by the words inside and outside. If you think of a donut, the hole is actually outside the donut, and all the dough is inside. In much the same way, our entire digestive tract (from head to tail) is outside, just as our skin is. All of the rest, the meat so to speak, is inside. All lining cells of the outside (epithelium) have some basic similarity, but undergo modifications depending upon their location and function. One of the major functions of our skin is to keep us from drying out; hence the relatively impermeable outer layer. The same cells on the inside of the mouth not only don't have to keep us dry, but have a distinct need to remain wet since their function is, in part, to lubricate food for its passage down the intestinal tract. Some of the cells are modified to form salivary glands which secrete copious quantities of lubricant (saliva). The esophagus, which passes from the mouth to the stomach, has a lining that is not too different from the inside of the mouth. The stomach and remaining part of the intestine have the function of digestion rather than abrasion resistance, as does the skin, the inside of the mouth, and the esophagus. The same modifications that help to keep bacteria from invading the skin also work to keep bacteria from invading the wall of the intestine.

There are other parts of the body where the "outside" pushes tunnels into the organism, with the tunnels still retaining some of the characteristics of "outside." The ear canal is a good example, as is the urinary bladder, the vagina, the windpipe, and the lungs. The lining of the uterus (womb) in which the child develops is also outside and, like the kangaroo's pouch, supplies a warm environment in which babies can grow. The fertilization of the egg ordinarily occurs on the outside. The ovary itself is "inside," but it sheds the egg into the fallopian tube (which is outside) and is fertilized there. The embryo goes to the uterus and sets up light housekeeping. It is partly because the embryo is kept on the outside that the mother does not ordinarily irnmunologically reject the infant. While this failure of the rejection mechanism is generally true, it is by no means always true. The exceptions can cause considerable trouble, particularly for the infant, since it is not in a particularly good position to defend itself.

When some of the cells of the placenta which are supposed to be outside lose their sense of direction and invade the inside of the mother (a rare event), we have a highly malignant tumor called a choriocarcinoma. This concept of "inside- and "outside" is useful because, as long as tumors stay outside they are easy to get at, can be removed surgically, and (unless they are pretty large) don't cause much trouble. It is when tumor cells penetrate to the inside, that a patient is in trouble. Tumors of cells that are normally on the inside, especially cells that normally move around on the inside, can cause real trouble.

There are cells whose business it is to wander around the body, Most of these are cells involved in defending an animal against injury or the invasion of microorganisms from the outside. The first line of defense is a white blood cell called the neutrophil, which is the main constituent of pus. It is produced in bone marrow and circulates in the bloodstream. The cells that ordinarily circulate are cells that will no longer reproduce (divide); they are "end cells." Occasionally, the cells that give rise to these neutrophils (a whole family of cells that goes by the name of the myeloid series) proceed to multiply in a manner that is greater than the rate at which they are used up. Whether they do this because they no longer respond to the feedback controls, or what the mechanism is, is unknown. When these myeloid cells multiply, they spill out of the bone marrow and, following their normal propensities, circulate in the blood. The condition produced is called mveloid leukemia, and it is a lethal disease.

The second line of defense against disease is a whole series of cells that are concerned with the manufacture of antibodies. The exact interrelationship of these cells is not too clearly understood, although a good deal of fruitful work is being performed in an attempt to understand it. The principal circulating cell is another white blood cell called the lymphocytes This cell appears to be able to recognize very specific types of invaders and respond accordingly. The lymphocyte is ordinarily a very long lived cell that circulates and recirculates in the bloodstream, apparently searching for any of the particular types of microorganism that will trigger it into doing its thing, which is to eventually manufacture antibodies against that organism (although when it does start to manufacture antibodies, it undergoes a considerable amount of change and ends up as a cell called the plasma cell. Nobody knows what happens to the plasma cell when its work is finished). When an animal produces lymphocytes far beyond what the animal can use, a condition called lymphatic leukemia is produced. Lymphocytes continue to behave in their usual manner and continue to circulate in the blood and, since there are too many of them, they really gum things up. There are some sedentary cells that look like lymphocytes, but do not circulate; and when these non-circulating cells are produced in excess, we have a condition called lymphosarcoma (a solid, non-circulating tumor), as distinguished from leukemia.

Both lymphocytes and myeloid cells can reproduce at varying rates. When the numbers of cells increase very rapidly the condition is referred to as "acute leukemia." When they increase slowly the disease is referred to as "chronic leukemia."

There are other types of wandering cells (macrophages), which we will not discuss here. When they do become tumors, they continue to wander, and are almost invariably malignant. There is no way of surgically removing a tumor of wandering cells. All treatments have to be based on some form of differential killing, either with chemicals or radiation. The rapidity with which leukemia kills is a function of how rapidly it is growing, which in turn, may be a function of the magnitude or type of the change that has occurred in the cells.

Some cells spread in very specific ways. There is a tumor called Hodgkin's disease, which is a tumor of one or more of the cells that are concerned with chronic inflammation, the kind of inflammation that stays around for a long time and gets better or worse slowly. This tumor apparently picks very specific places to grow. Some tumor cells prefer to live in lymph nodes and some prefer to live in the spleen. In the early stages of this disease, the tumor may be confined to several very specific areas. When it overgrows its specific sites it spreads all over the body to all organs.

Cells of the skin or intestine (remember these are both on the "outside" of the organism) naturally divide at a very rapid rate. They have to, in order to keep pace with the number of cells that are continually being sluffed off. In order for these cells to produce a malignant tumor, it is not necessary that any change in their rate of cell division occur; but it is necessary that they, in some way, forget where they are supposed to be and decide that they want to live in the "inside" of the animal. Living in the inside of the animal and dividing at their naturally rapid rate will produce all sorts of problems. If, besides deciding that they want to live in the inside of the animal, they also develop the capacity to grow in places where they would ordinarily not do so, such as the lung, the individual bearing these cells is in real trouble.

We have talked about how important it is for cells that are on the outside of the animal to know enough to remain outside (i.e., not to invade the inside of the animal). These relationships are established fairly early in embryonic development, and one of the most interesting aspects of this is the question of what keeps the skin side outside and the inside inside.

Malcolm Steinberg, at Princeton, has taken large numbers of different types of embryonic cells and mixed them together. The loose cells aggregate into a ball, with one type of cell on the inside, and the other on the outside. He has found that cells behave in much the same way as oil droplets in water, in that there is a clear relationship as to which substance is inside and which substance is outside, depending on their physical properties. He has developed a way of measuring cohesiveness of different types of cells grown in test tubes, and can predict on the basis of their cohesiveness what will happen when you mix two different types of cells together: which type of cell will find itself on the outside and which type of cell will find itself on the inside. This type of work performed on skin and skin tumors and their relationship to connective tissue may very well explain what types of changes are necessary in skin cells for them to develop the capacity to move into the inside of the animal.

The concept of an animal having an inside and an outside is useful because it defines one of the most important problems in differentiation. We all of us started as a single cell, and in the process of "differentiation," this single cell divided, not only into a large number of cells, but into cells of different kinds. These different kinds of cells come together in a particular arrangement according to information that is already in the cells (in their genes). All that I can do is marvel at the precision and order with which this is done. I cannot explain it --nor can anyone else. Science has done a superb job of finding out how things happen (this is the main accomplishment of experimental embryology to date), but we have discovered very little about why they happen.