ARTICLES

Is the body its own best doctor?

Some of the most exciting medical news ever made may follow fresh discoveries about the body's own natural defenses. They offer hope of—

SIDNEY KATZ November 22 1958
ARTICLES

Is the body its own best doctor?

Some of the most exciting medical news ever made may follow fresh discoveries about the body's own natural defenses. They offer hope of—

SIDNEY KATZ November 22 1958

Is the body its own best doctor?

Some of the most exciting medical news ever made may follow fresh discoveries about the body's own natural defenses. They offer hope of—

SIDNEY KATZ

There’s a good chance that we're on the

verge of the biggest medical breakthrough of the century. The area which may yield this rich harvest in human health is the immunological mechanism — the body’s built-in natural defense against disease. If the hopes of present research are realized we may soon have the means to curtail or even wipe out a long list of illnesses that have been hitherto unpreventable.,

Throughout medical history doctors have been making use of the immunological mechanism to protect us against disease. There are now vaccines which shield us against polio, whooping cough, smallpox and diphtheria. They all work in the same manner. The body has a defense mechanism which immediately springs into action when a foreign substance invades it—be the invader bacteria, a virus or an allergic substance like ragweed pollen.

Millions of antibodies (proteins produced by the plasma cells in the body) pour into the blood stream to grapple with the invader. For each type of invader (or antigen, as the scientists call it) a specific kind of antibody is produced. Once created the antibodies remain in the body for a lifetime ready to do battle against the invader again. The effectiveness of these antibodies is usually so great that most of us have had mild attacks of serious diseases without even being conscious of the fact. This is proven by the high

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■ protection against some cancers ■ an answer to schizophrenia ■ a safe way to graft tissue between persons ■ immunity to allergies before birth ■ a remedy for “lethal” doses of radiation

Is the body its own best doctor?

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‘There’s alreadysome reason to believe - that a natural defense mechanism exists against cancer”

proportion of people who have antibodies of polio, TB and infectious jaundice in their blood.

We are learning new things almost every month about the body's defense mechanism. Because of this, long-cherished goals in medicine may now be within our reach.

Here’s a partial listing:

• A safe and certain protection against many types of cancer may be devised. There’s already reason to believe that a natural defense mechanism exists against cancer. The person who is “cancer-prone,” goes the theory, is one in whom the defense mechanism is not working. Using laboratory animals, it has already been proven possible to cure some types of transplanted cancer by giving the dormant defense mechanism the impetus it needs to send it into action. In controlled experiments with humans it has been found possible to immunize them against transplanted tumors, although as yet no means has been found to grant immunity against selfgrown tumors.

• It is possible that some cases of schizophrenia—the most common of the serious mental illnesses—represent a failure of the body’s defense system. Doctors theorize that schizophrenia may be caused by an elusive chemical which they have tagged “P.” The body of the normal person, they speculate, fights “P” and builds an immunity to it; the body of the schizophrenic is helpless against it. Two significant facts point up the possibility that the chronic schizophrenic's immunological defense system is out of kilter. The first is that the chronic schizophrenic usually shows no reaction to LSD-25 — a drug which seriously disturbs the normal person. The second fact is that the schizophrenic rarely develops allergic conditions—a strong indication that his immunological system may be functioning abnormally. When this puzzling situation is fully explained, we may be closer to the prevention of one of the toughest and greatest problems in mehtal health.

•* Paradoxically, there are times when the body's defense mechanism works too well, and the cure is worse than the ailment. Allergic reactions are a prime example. Hives, eczema, asthma, etc., are merely bodily symptoms of the defense mechanism at work trying to oust an invader. The possibility now exists of protecting the individual for many years—if not for life—against allergies. This would be done by the newly discovered technique of acquiring immunological tolerance, i.e. treating a living body so that its defense system won't react to a foreign invader. This kind of tolerance may be granted by treating the child at birth. Another method would be by treating the child before birth by altering the mother’s diet or injecting her with certain substances or by some other means not yet evolved.

• Acquired tolerance points toward other medical blessings as well. Hitherto, a person in need of a skin graft has had to depend on skin from another part of his own body. The one exception was if he happened to be an identical twin; in that case he could successfully accept a graft from the other twin. The reason that skin grafts ordinarily don’t succeed is that the donor's skin

contains antigens which stimulate the host (the person receiving the graft) to manufacture antibodies which fight the graft and ultimately cause if to slough off. By using new techniques based on our expanding knowledge of the body's de-

fense mechanism, it may now be possible to freely transplant skin — and even organs like kidneys — from one person to another or even from animals to persons.

• Our newly discovered secrets about

the body's defense system may also make it possible to cure people who have received "lethal" doses of radiation. (Excessive radiation causes death by destroying the cells which manufacture blood.) This would be done by injecting the pa-

tient with blood-manufacturing bonemarrow cells from a healthy person. Hitherto, these cells would only function for a limited time because the donor’s cells and the host’s cells were incompatible. This produced antibodies which, in turn, led to “secondary diseases” and death. The use of new techniques points the way to a permanent cure for radiation sickness.

The recent discovery of one simple fact has made acquired tolerance possible. This fact is that the defense mechanism does not begin to operate until birth or shortly after birth. The exact time when the immunity mechanism matures and is able to fight foreign invaders by spewing forth antibodies varies with each species. In man, the time is some period soon after birth. In mice, it’s believed that the defense system remains inactive until a few days after birth. Rats and rabbits evidently have no immunity mechanism until they’re about a week old.

If foreign matter is injected into the body during this period before the immunological mechanism has matured, the body will not fight it. No antibodies will be produced. There will be no reaction. The body will accept this material as part of itself at that moment and, with some reservations, as long as it lives. Scientists have tagged this phenomenon “actively acquired tolerance.”

Researchers at the Princess Margaret Hospital, Toronto (formerly known as the Ontario Cancer Research Institute), have injected unborn mice with horse serum—a procedure which usually produces a strong physical reaction. (Serum is the watery portion of blood left after the blood coagulates. The serum of horses is widely used to prepare protective “shots.”) The foetal mice did not react to the serum, which was not unexpected since their immunological mechanism had not yet matured. However, some weeks after birth when the mice were given another dose of horse serum, they did not react to it despite the fact that their immunity mechanism was now fully grown and capable of reacting to other substances. They fully tolerated the horse serum.

In another experiment, a few cancer cells were implanted in embryo mice. After they were born, tumors of the same type were implanted in the mice and practically all of them grew vigorously. The mice had virtually no defense against them. In other words, because a sample of the antigen was introduced into the mouse’s system before immunological maturity, the mouse tolerated this particular type of antigen

throughout its life. This experiment was performed with a type of cancer which is most difficult to grow on an untreated, adult mouse. The immunity mechanism practically always fights it off.

The ability to make a living body tolerant to any antigen by injecting it with that antigen before its immunity mechanism matures is, in the words of one doctor, “a double-edged sword.” One is the possibility of banishing allergic reactions. Almost everybody, nowadays, is allergic to something—specific drugs or foods, alcohol, dusts, pollens, synthetic materials or animal hair and dandruff. When the body comes in contact with any substance to which it is sensitive—by inhaling, touching or eating— the body’s defense mechanism immediately springs into action. This "defense” sometimes results in symptoms as disabling as hay fever, migraine headaches, eczema and asthma. Sometimes, allergic reactions cause death: in the last five years fifty-two people have died of bee bites in the United States and similar fatalities have also been reported in Canada. In children, allergic reactions can stunt growth and lead to the faulty development of bones and muscles.

With our growing knowledge of acquired tolerance it may be possible to ward off these unhappy effects. Practically all things people get allergic to can be injected at birth. Nor would it be necessary to inject a hundred different substances into the newborn infant at random. Geneticists have found that many specific allergies run in families. Some estimates claim that at least seventy-five percent of allergies can be traced to parents. Thus, offspring could be injected with the substances to which their family histories indicate they may be allergic and rendered tolerant to them.

There is evidence that nature sometimes follows this technique in bestowing people with tolerance to certain antigens. A case in point is the skin disease caused by a highly potent antigen found in poison oak, poison ivy and mango fruit. It has been noticed, in a California study, that California residents who had been born in Hawaii or the Far East suffer from poison-oak irritation far less frequently than the native-born. Furthermore, patch tests confirmed the fact that they were far less sensitive to this group of plants known as the Rhus.

What could be the explanation? Dr. Rudolf L. Baer, a New York dermatologist, speculates that the people born in Hawaii and the Far East were exposed to mango fruit—probably the most powerful of all the Rhus materials — during pregnancy and childhood. “The mothers were exposed to mango fruit and ate it

during pregnancy and this may have had an effect in creating a tolerance for the Rhus antigen in the offspring,” says Baer. This view is underscored by other studies which show that you can prevent future allergic reactions in a child by manipulating the diet of the pregnant mother.

At Princess Margaret Hospital, staff scientists have injected the foetuses of mice, rats and rabbits with various antigens, working particularly with horse serum. When the animals were born, they had no horse-serum antibodies, indicating that they were tolerant to this substance and completely accepted it. When older, the same mice were given another dose of horse serum. There was still no physical reaction or physical discomfort. On the other hand, two successive shots of horse serum given to adult mice produced an immunological reaction so great that death usually resulted.

This technique of acquiring tolerance to horse serum may be of great future benefit to man. People who suffer deep body wounds are injected with antitetanus antitoxin which is made with horse serum for reasons of practicality and convenience. (So are diphtheria antitoxin and other immunological products.) This treatment is prescribed to ward off lockjaw, caused by lethal bacteria. However, many individuals react severely to the anti-tetanus preparation, particularly if they have been sensitized to it by a “shot” during childhood. The shock is often so great that it's suspected that these allergic reactions cause more deaths than the actual injuries which are being treated. A small dose of horse serum at birth, for the purpose of inducing tolerance, might rule out the possibility of such a severe reaction for the duration of the person's life.

One of the most useful applications of our newly found knowledge about immunity and tolerance may be in the transplantation of skin, kidney, lung, heart and other tissues. The simplest form of transplantation is skin grafting. This consists of laying a piece of skin over the area to be repaired and keeping it there under light pressure until the connectivetissue fibres become knitted to the skin underneath. Early surgeons thought it possible to exchange grafts between people (homografts) and. indeed, even between people and animals. However, they soon learned that they were wrong. The two pieces of skin were incompatible. The immunity mechanism of the host would reject the foreign matter. After a week or so. the skin graft wotdd become puffy and inflamed and drop away. It soon became evident that the only grafts possible were autografts (with skin taken from another part of the person's body) or skin transplanted from one identical twin to another.

Two new techniques may usher in a whole new era in tissue transplantation. The first is that it should be possible to use grafting material from embryo or newborn animals because this material does not yet contain antigens which create antibodies in the host, which in turn leads to the sloughing off of the graft. Second, it is now possible to make use of the principle of acquired tolerance. At birth, it may be discovered that an infant is going to need extensive skin grafting. It might then be possible to inject him with skin cells from an adult who is going to be his donor at some future time. When the skin graft is actually carried out the infant will tend to accept it because he has been rendered tolerant to tissue from his future donor.

Some of the future developments in transplantation are foreshadowed in a recent report by an English scientist, Dr. R. E. Billingham, and his associates. He

records that mice, rabbits, rats and birds were injected with blood cells from adult members of the same species during the foetal period. Later, these animals successfully accepted skin grafts from these same adults who belonged to a similar strain.

Because of the increasing number of injuries due to fires and accidents, there is a constant demand for human-skin substitutes. It was only natural that medical researchers should be attracted to embryo material because of its freedom from trouble-causing antigens. In recent years, Dr. A. N. Silvetti and colleagues of the Naval Medical Research Institute, Bethesda, Maryland, have been using the skin of embryo calves obtained from slaughtered cows, on human beings. Silvetti is enthusiastic about the material. "It's hairless, clean, soft, pliable, transparent and light colored,” he says. He used it to repair a skin wound on the leg of one woman; after five weeks he reported that there was no inflammation and that there was now a thin layer of normal skin tissue growing. Skin from an embryo calf has already been used in experimental laboratories to correct skin defects in mice, rabbits, rats and dogs. It has also been used as a temporary biologic dressing on human wounds on the thigh, arm and scalp. "In none of these patients,” says Silvetti, “were there any obvious or apparent foreign-body reactions to the bovine material.”

From mice to men

Our newly acquired information is being applied to the looming problem of preventing death from excessive radiation. Death is caused because of damage done to the blood-forming cells which are principally located in the bone marrow. In past laboratory experiments, attempts have been made to keep irradiated mice alivé by injecting them with bone-marrow cells from healthy, adult mice of the same strain. The early results were encouraging. The freshly injected cells caught on and began manufacturing blood. However, in time, the injected cells recognized the host cells as foreign and began to manufacture antibodies against them. This led to "secondary disease” and ultimately death. Recently, medical researchers at the Atomic Energy Research Establishment at Harwell, England, have been injecting bone-marrow cells from foetal mice into grown mice whose own blood-manufacturing cells had been destroyed by massive doses of radiation. Lacking defense machinery, these foetal cells don’t engage the host in battle. The result has been a much higher rate of survival among animals who have received "lethal” doses of radiation. Already, in England, experimentation is under way with the use of human foetal material to save the lives of human beings who have been excessively irradiated.

Current exploration of tolerance and immunity suggests new avenues of progress in the fight against cancer. Many cancerologists now share the opinion of Dr. Max Cutler, former director of the Chicago Tumor Institute, who says that "a defense mechanism against cancer exists in the body and it may be that the cases of cancer we see in the clinic are only the ones where the defense mechanism failed.”

Dr. Philip West of the University of California cites a series of autopsy studies done on a number of males past fifty who died of miscellaneous causes other than cancer: forty-five percent of them were found to have cancer of the prostate gland. Yet, says West, "obviously most of these cancers remained station-

ary or regressed and the individual lived his normal life span oblivious of the fact that he may have had cancer for twenty or thirty years.” In a mass detection survey a large group of women were discovered to have cancer of the cervix. Their cases were studied for a number of years. In only twenty percent of the women did the cells proliferate to the point where they required treatment. In the remainder, the growth disturbance was self-controlled and vanished. West concludes, "It is very possible that all of us may have had or will have some form of cancer but because of a built-in natural defense mechanism we will never know it and die of an unrelated cause.”

The most dramatic — as well as the most mysterious—examples of the defense mechanism at work, are the cases of “spontaneous remission” of cancer. In the past fifty years at least 120 case histories have been gathered which describe patients who were given up by doctors but survived and went on to enjoy years of good health. It was as though, at the eleventh hour, the body mobilized its defensive machinery to cast out the tumors which had gained a firm foothold. A typical case of spontaneous regression, gathered by Prof. William Boyd, a former University of Toronto pathologist, concerned a young woman in her thirties who had tumerous growths in her breast, upper arm, abdomen and groin. Doctors pronounced her incurable. Yet, she survived the delivery of her child and, when seen four years later, the masses of growth had vanished and she was perfectly well. Commenting on this and similar cases, Dr. Boyd says, “Nothing in nature is ever really spontaneous. There is always a cause.” He speculates that at some point in the disease, some part of the tumor cells causes the formation of specific antibodies which eventually conquer the cancer cells. He advocates research to find out exactly how the tumor cells or some fraction of them “can be used as an antigen for stimulating the natural defenses against the invading organism.”

It may be that Dr. Gordon Murray, a brilliant sixty-two-year-old Toronto surgeon, has discovered a way of triggering the body’s natural defenses to fight cancer. Recently, Murray announced that he had inoculated horses with human cancer tissue, and, after the animals had had time to manufacture antibodies, he bled them, and extracted serum from the blood. He then injected this anti-cancer serum into terminal-cancer patients in increasing doses for twenty-one days. While Murray claimed no cures, he says that patients lived up to three years after other forms of treatment had been abandoned.

Probably the most ambitious attempt to unravel the secrets of the body’s defenses against cancer is being made at the Sloan-Kettering Institute for Cancer Research, New York. Hundreds of human

volunteers are helping the scientists to answer the basic question, "What are the differences in the defense mechanism of tfhe cancer-prone and the cancer-free person?”

The present experiments started with a group of fifteen hospital patients with far-advanced, inoperable cancer. Clusters of cancer cells were planted in the skin under their forearms. The transplants spread and grew until surgeons removed them. "If bodily defenses against transplanted cancer exist,” reported one doctor. "then these patients certainly lacked them.” Next, the Sloan-Kettering scientists visited Ohio State Penitentiary and injected the same stock of cancer cells into fourteen healthy prisoner volunteers. Unlike the hospital cancer patients, this group had a defense against the disease: the transplants refused to grow and within a month practically all of the cancer transplants had died. Three months later, the Ohio volunteers were again inoculated with the same cells. This time their defense mechanisms acted even more quickly; in a week all the cancer cells died.

From these first experiments, the Sloan - Kettering team concluded that healthy people have some defense against cancer; that the defense against a specifictype of cancer implant can be strengthened by a re-inoculation. But they noted, in one of their reports, that a number of general questions had to be answered: had they created an immunity to cancer in the same way an immunity to polio, diphtheria or typhoid fever can be created? And would immunity to one kind of cancer give any protection against others?

On their next trip to the Ohio prison, the researchers took with them seven different kinds of human cancers. This time there were fifty-three volunteers, half of whom had previously received inoculations. Some of these veterans received the same type of inoculations they had previously received; others, different strains. The veterans receiving the new strain conquered the cells faster than the volunteers who were being injected with cancer for the first time. On the other hand, they were slower in killing them off than men receiving a second injection of the same cancer cell type.

"This could be regarded as a major discovery,” the scientists report. It appears that if you can develop immunity to one type of cancer, you succeed—at least partially — in developing immunity against all types. The results also suggest

that all kinds of cancer have something in common which triggers the body to resist. The next phase of the enquiry is to find out what part of the cancer cell has this immunizing power. Perhaps if it could be identified and extracted it might be effective against real cancers as well as transplanted ones.

Another search being conducted by the Sloan-Kettering doctors is to discover the precise biochemical ways in which the Ohio volunteers and the cancer patients differ. One startling difference which was almost immediately spotted related to a chemical found in the blood stream known as properdin. The volunteers had an average properdin level of seven units; on the other hand, advanced cancer patients seemed to he deficient in properdin—they averaged only two units.

Laboratory results with properdin have fired the interest of the investigators. An injection of a small amount of zymosan —extracted from yeast cells — has the effect of raising the properdin level in the blood. A group of mice suffering from a highly malignant type of cancer that usually kills ninety-five percent of them within three weeks, were given small amounts of zymosan to raise their properdin level. In every instance, the cancers were dissolved and the mice were completely cured. In another experiment, it was noted that the properdin level in the blood of mice in which cancer was growing gradually decreased as the tumor increased in size.

Will transfusions of human properdin, in amounts large enough to restore it to the normal level, help the patient with advanced cancer? Sloan-Kettering scientists hope to answer this question soon.

Properdin, however, is only one aspect of the enquiry into the body's defense against cancer. The virus now occupies a prominent place on the cancer-research stage. It has been definitely established that at least one form of mouse leukemia is caused by a virus. Furthermore, a vaccine — prepared like the Salk polio vaccine — will protect ninety percent of mice against this one form of leukemia. This virus is being carefully studied in laboratories all over the world, particularly its immunological powers and traits. Somewhere in the resulting data may lie the secrets of how the body defends itself against other types of viruses—some of which may be the cause of human cancer. If this research is successfully completed we may realize the centuries-old dream of finding a vaccine against cancer, it