Frontal Attack

(See Cover)

Even as hospitals go, Manhattan's famed Memorial Hospital is not a light-hearted place. Its corridors never echo with the happy sounds of a maternity ward. No one is there because of minor ailments or for a good rest. Most of the patients know that their chances of recovery, though somewhat better every year, are poor indeed. Visitors passing through the lobby often look stunned by grief. Memorial is a tragic place because its patients are victims of cancer.

Room 1O2L, a short walk down an immaculate corridor, is one of the most cheerful-seeming places in the hospital. Divided by stiff brown curtains into examination booths, it rings on Friday mornings with the voices of children. A little boy with a Tommy gun shoots sparks at a white-coated doctor, and a plump little girl cradles her doll. In a corner, a nurse in a starched white uniform peers through a microscope and makes a click-click sound with a small, sharp-voiced machine. She is counting in some child's blood the deadly white cells of leukemia: cancer of the blood. All the children in 1O2L of a Friday morning have leukemia, for which no cure is known. All of them, as medicine's knowledge stands at present, will die of the disease.

Tower of Hope. Last week, as he does every week, a man with short-cropped, iron-grey hair, blue eyes and an easy smile stopped in at Room 102L. Dr. Cornelius Packard Rhoads, director of Memorial, the world's biggest cancer hospital, is an outstanding symbol of medicine's determined campaign against a disease which causes one out of every seven deaths in the U.S. Dr. Rhoads also heads the Sloan-Kettering Institute for Cancer Research, whose 14 stories rise beside the hospital. In this tower of hope, the world's most ambitious cancer research laboratory, highly specialized scientists and technicians experiment endlessly in the war against cancer; from it have come strange new treatments that have, so far, kept many leukemic children alive.

"We can help only 25%," says Dr. Rhoads, "and they have remissions only. Their disease will recur and recur, perhaps in more violent form. Some people ask, 'Why keep them alive, if they must die eventually?' But we're moving faster now. Perhaps, before they exhaust their last remission, we'll have something really good. And you've seen how happy they are."

The Wartime Method. Dr. Rhoads's jobs as head of Memorial and of Sloan-Kettering allow him little time for his favorite recreation--sailing. Like most men named Rhoads, he is called "Dusty" by his friends. Born in Springfield. Mass. 51 years ago, he graduated from-Harvard Medical School in 1924. He has long been a successful medical scientist, and today he could be mistaken for the go-getting president of a big university.

In World War II, Dr. Rhoads was chief of the Medical Division of the Army's Chemical Warfare Service. The gas program turned out to be "preventive" only; the enemy did not use gas. But the experience made a lasting impression on him. He came away from war work with enormous respect for what can be accomplished when scientists, who are notoriously in dividualistic, get together. Driven by wartime urgency, the scientists abandoned their jealousies and rivalries, submerged their temperaments and attacked each problem cooperatively from every possible angle. High-pressure wartime science achieved in a few years what would have taken decades of sauntering peacetime effort. Why not, thought Rhoads, use the wartime method on cancer?

What Dr. Rhoads thinks he is apt to say --loudly, clearly and often to a great many people. His persuasive tongue, a rare gift among scientists, had some effect. In 1945 Alfred P. Sloan Jr., chairman of the board of General Motors, gave $4,000,000 to set up the Sloan-Kettering Institute, with Rhoads at its head. Other sources of funds promised lavish support. The impressive building was finished 18 months ago, and Rhoads began assembling a staff. "All I can do," he says, "is pick good men, give them opportunities and help them keep pointed at the target."

Among cancer men, who carry on their research work individually and in teams across the country, brisk Dr. Rhoads is not universally popular. A few worry because they think his position gives him too much power over cancer research. Rhoads himself knows that he runs the risk of being called highhanded and arbitrary, the head of a vast research organization that stamps out individualities. But he hopes that Memorial Hospital, with its pathetic patients, will supply some of the qualities of a wartime emergency.

"Some authorities," says Rhoads,"think that we cannot solve the cancer problem until we have made a great, basic, unexpected discovery, perhaps in some apparently unrelated field. I disagree. I think we know enough to go ahead now and make a frontal attack with all our forces. Anyway, that's what we are doing. We'll follow every promising lead, and we know a lot of them. If the ivory tower men solve the problem ahead of us, we won't feel we've wasted our time."

Gangster Cells. The "cancer problem," as pathologists call it, is one of the strangest and subtlest that medicine has faced. Cancer is not an outside enemy that can be fought in the open like a foreign invader. It is civil war among the body's own cells, and it runs through all of nature like a red fiber of ruin spun into the thread of life. All vertebrates, including frogs and fish, get cancer. In all probability, the experts say, invertebrates and plants have cancer too.

As a normal thing, the several hundred trillion cells in a human body cooperate loyally, subordinating themselves to the body's higher life. Their functioning and their usually slow rate of multiplication are controlled, most scientists believe, by the chemical hormones which are poured into the blood by a set of regulating glands.

Sometimes, for reasons which medicine does not yet understand, a cell turns out to be different from normal cells. Most such "mutations," less competent than the normal cells, die and are absorbed by the body. But occasionally a variant cell appears that is disastrously competent.

Something in its chemistry allows it to defy the hormones that regulate the growth of ordinary cells. It multiplies wildly, growing into a useless mass of disorderly tissue. The tumor pushes among the normal cells, presses on nerves, thrusts organs aside or invades them. Often the gangster cells get into the blood and spread around the body like seeds carried by the wind. Where they lodge they grow into "metastases"--secondary tumors as lawless as the first one.

That is cancer: war between the body and its rebel cells. But it is not a two, sided civil war, because the body has almost no defenses. The body creates no antibodies against cancer as it does against diphtheria or typhoid. It builds no tissue walls to confine the destructive cells. It feeds them well, allows them to grow unchecked, and dies helplessly when they disrupt some vital function.

"The Nazis were rather like cancer," says Rhoads, growing philosophical as all scientists are apt to do when they think about cancer. "Starting with a variant cell, Hitler, the Nazis multiplied throughout the German nation, bringing it to destruction. It took external forces to kill the Nazi cancer."

Knife & Radiation. "External forces" are the business of Sloan-Kettering Institute and all the other centers of cancer research, which are spending something like $50 million in the U.S. annually. At present the only known cure for cancer is destruction: the surgeon's knife or radiation (X rays and radium). Such methods work well with some forms of cancer. Skin cancer, for instance, can nearly always be removed so completely that it does not recur. Other accessible cancers can be dealt with too, and surgical methods are improving constantly. A recent advance saves many patients who have a vital artery that has been attacked. An "artery bank" supplied from such sources as amputation cases makes it possible for the surgeon to replace a cancerous artery almost as if he were a plumber replacing a rusted pipe.

Not long ago, Memorial's doctors noticed that cancer patients, often reacted well after a serious operation, but died a few days later for no apparent reason. Sloan-Kettering's research men went to work to find an explanation, found that in such cases the patients had died because of a deficiency of potassium in the blood. When potassium was added in new cases, the patients picked up quickly and survived the operation. Dr. Rhoads believes that such improved surgery and treatment, combined with sufficiently early diagnosis, may save from cancer one-third to one-half of the people who now die of it. That would mean saving the lives of 6,000,000 to 9,000,000 Americans now living who are destined, on the basis of present statistics, to die of cancer.

Differential Effect. Surgery cannot help the other 9,000,000. Many cancers involve vital organs that cannot be disturbed, or metastases which spread so quickly and widely throughout the body that the surgeon cannot find and remove them all. To deal with such cancers some agent is needed that has a strong "differential effect," i.e., that kills cancer cells without hurting normal tissue. A few such drugs are already known, but they are only a start, and not good enough.

The trouble is that cancer cells are very like normal cells. An agent that hurts one generally hurts the other. Still, the gangster cells have differences. The very fact that they grow rapidly in a chemical medium, the blood, in which normal cells grow slowly, is sufficient proof that they are different. To find and exploit the differences is the chief goal of Sloan-Kettering Institute. The problem is being attacked at all levels--from simple testing of promising drugs to long-range exploration of the internal workings of cells.

Every week dozens of new chemicals come to Sloan-Kettering from commercial laboratories, chemical houses, university scientists and medical men. Each is catalogued and given a number (to head off charges of favoritism). The more interesting ones, thought to have strong biological effects, are tried on experimental cancers planted in white mice.

Girls & Mice. This testing is a mass-production process which would be impossible on such a scale in a smaller laboratory. Girls in white uniforms sit at a table with cages of mice before them and bits of mouse cancer in glass trays.

Deftly a girl picks up a cancer fragment with a trocar (a tubular needle with a plunger inside). She grabs a faintly squeaking mouse, holds it by the scruff of its neck, efficiently jabs the trocar into the skin of its belly and up under a front leg. She plants the cancer by pushing it out with the plunger. Then she reaches for another mouse.-

When the cancer has had time to "take," the mouse is injected with a just-under-killing dose of the chemical to be tested. After a week or so, a girl kills the mouse by crushing its fragile skull. Then she slits open its belly skin and measures the cancer, which is usually by this time a grey-pink, rounded mass as big as a thumbnail. If the tumor has disappeared or has not grown as much as expected, the chemical is listed as promising enough for further testing.

Eggs & Tubes. Another type of testing is done on eggs. A girl technician examines a fertile egg under a strong light, finds the developing embryo, and cuts a square hole in the shell above it. She plants a bit of cancer on the embryo, and seals the hole with a glass window stuck on with wax. The egg is put in an incubator. As the embryo grows, the cancer grows too. The embryo's blood vessels turn aside to supply the cancer, which frequently grows until it is nearly as big as the chick. Drugs are tested by injecting them into the egg yolk, and noting through the window what they do to the cancer.

Another method is tissue culture. Bits of cancer tissue are stuck to the side of a test tube. A nutrient solution (made of such unlikely ingredients as extract of human placentas) is added. The tube is sealed and put on a vertical merry-go-round in an incubator. As the merry-go-round revolves slowly, the solution washes over the cancer tissue, which grows vigorously just as if it were in a living body. Drugs can be tested against it simply by adding them to the solution.

Sloan-Kettering now has 2,300 chemical agents on file, and has already tested some 1,500. Six of them proved to have a good "differential effect" against one or more types of mouse cancer. A couple of dozen had some lesser effect. According to Dr. C. Chester Stock, head of the Division of Experimental Chemotherapy, this record is by no means discouraging. As the records and experience accumulate, the scientists are learning how to predict whether a compound is worth testing. If a new one has a slight effect, one of its close relatives may prove better. And each slightly successful drug sets biochemists to figuring out why it worked at all.

Cell City. Long-range figuring-out is the duty of such men as Dr. George B. Brown, head of the Protein Chemistry Division. Dr. Brown and his assistants are studying the chemistry of both normal and cancer cells, looking for differences that they may exploit.

Cell chemistry is a maddeningly complicated study. It is known that cells contain certain chemicals, but they are not mixed together haphazardly like dissolved salts in a chemist's beaker. Each cell is like a great, complex metropolis. The individual citizens (atoms) are organized into intricate groups like the people of the city. Some groupings (e.g., the three-atom molecule of water) are as small and tight as families. Others are larger, like all the workers in one factory. The various groups interact constantly, their links forming and dissolving as the cell lives and grows. Certain single large molecules (analogous to the city government) are thought to affect all the cells.

To get the most rudimentary understanding of the workings of the living, changing cell is enormously difficult. It would be even harder without a new tool: nitrogen 15, a stable (nonradioactive) isotope of nitrogen. Chemically, nitrogen 15 is exactly like the common nitrogen 14. The cells cannot tell the difference. But since it is slightly heavier, nitrogen 15 can be measured accurately by a balky and expensive instrument called a mass spectrometer. If compounds containing nitrogen 15 instead of ordinary nitrogen are fed to cells, the scientists can tell with the mass spectrometer whether the cells have accepted them as food.

Such work is slow and expensive: nitrogen 15 costs $1,000 for a single study. But already Dr. Brown's group have had one outstanding, success in their study of a cell's reproductive system. They used an artificial compound called 2,6-diaminopu-rine, not yet isolated in nature, which they thought had a momentary existence inside the cell. The organic chemists synthesized some of this compound and turned it over to the chemotherapists. They thought that it might have the sought-for "differential effect" on lawless cancer cells.

Sure enough, "2,6" prolonged the life of leukemic mice by 60%. It destroyed or controlled rat tumors. It killed other tumors in test-tube cultures. On human patients, it acted as a palliative, but not a cure. It has secured "remissions," for instance, for a few leukemic children.

Promising Molds. Dr. Rhoads and his associates believe that no possibility, even faintly promising, should be neglected. One long shot is to look for something in the secretions of molds. One such secretion, penicillin, has a differential effect on bacteria: it kills bacteria but leaves human tissue unharmed. Molds might conceivably produce something with a differential effect on cancer cells.

In a cold, air-conditioned room in Sloan-Kettering, various molds (green or white mats) are growing in flasks. The program is still young, but already one mold has been found that secretes a substance with a slight differential effect on mouse tumors. Dr. Rhoads does not even want to talk about it yet. He has no "cancer penicillin."

Behind a door marked "No Visitors" (no one may enter who has not been properly immunized), works attractive Dr. Alice Moore, a leading virus fancier. "I'm a virus girl," she says, "so I thought I'd ry 'em." She tried influenza virus on can-:erous mice. No effect. She tried the virus of herpes (inflammation of the skin and mucous membranes). No effect.

Then she turned to the deadly virus of Russian spring-and-summer encephalitis, injected it into the abdominal cavity of cancerous mice. In about two days the firm, round tumors turned into blobs of pus. All the cancer cells apparently died. But the virus then went on and attacked the nerves and brain. Four days later the mice, apparently cured of cancer, died of encephalitis. Nonetheless, the virus had shown a dramatic differential effect. It went first to the tumor and thrived there before attacking the brain.

Try the Viruses. There is a long list of things that Dr. Alice can do now to exploit her discovery--so many things that Dr. Rhoads is enlarging her dangerous laboratory. One is to try the encephalitis virus on monkeys. The laboratory strain has lived so long in mouse brains that it may have lost its ability to attack primates. If it proves harmless to monkeys, it probably will not hurt humans. The final step will be to try it on human cancer patients to see if it attacks their tumors.

Another thing that Dr. Alice hopes to do is to grow her virus for a long time in mouse tumors, transferring it from mouse to mouse as the tumors die. When grown on new food, viruses often change their ways. Dr. Alice hopes that the encephalitis virus might be taught to give up its taste for brain tissue while increasing its appetite for tumors.

If all these methods fail, there are plenty of other viruses to try against cancer. Some of them, comparatively harmless to normal human tissue, may attack tumors. If some such virus could be found or developed, it would be an ideal anti-cancer drug. Circulating through the body like a ferret through rat holes, it could hunt down every gangster cell.

Search the Soil. One of the most interesting programs at Sloan-Kettering is concerned not with the cancer cells, but the "soil" (as Dr. Rhoads calls it) in which they grow. Normal human cells often look startlingly like small, one-celled animals. But they are not free agents. Their growth is controlled and limited by the hormones in the blood. The most important hormones come from the gonads (testes and ovaries) and from the adrenals (small glands attached to the kidneys).

It has been known for a long time that the steroid hormones (socalled because they contain the "steroid" nucleus in common) are closely connected with cancer. The administration of sex hormones can both cause and prevent certain cancers in mice. Some cancer researchers hold to the theory that a complete understanding of the steroid hormones might tell why cancer occurs, how to cure it, perhaps even how to prevent it. The difficulty is that there are a great many steroid hormones. Their study requires such special methods and special apparatus that steroid work has become a recognized sub-subdivision of biochemistry. At Sloan-Kettering the experts in this mysterious field sit together at luncheon, speaking a special language.

Leading steroid man at Sloan-Kettering is short, round, German-born Dr. Konrad Dobriner. The raw material of his science is human urine, in which are found steroid "metabolites" (breakdown products from the hormones that the body has used and passed on). Dobriner's assistants collect urine for months or even years from the people they intend to study. They extract the steroids by a long series of tedious techniques, and identify them by their characteristic absorption of infrared light.

Glandular Orchestra. Dobriner has already achieved startling results. The urine of each person has a different steroid pattern, but in healthy, normal males & females there is a general similarity. In cancer patients, however, there is a striking difference. A new steroid, 11 hydroxy-etiocholanolone, almost always absent in healthy persons, shows up in about two out of three cancer patients.

A remarkable discovery came when a woman from whom Dobriner had been collecting urine for several years suddenly developed cancer of the breast. Dobriner found, on examining the stored extract from her urine, that she had been excreting the uncommon steroid for at least three years before her cancer developed. The tumor was removed surgically and the woman is now apparently in perfect health. But she still excretes the cancer-pointing steroid.

It looks to Dobriner as if the presence of the uncommon steroid may indicate not only cancer but sometimes an abnormal hormone situation that leads to development of cancer. "The endocrine system," he says, "consists of a number of glands that should be in harmony, like a symphony orchestra. We want to prove that in cancer the orchestra is haywire."

Dobriner points out that steroid identification is not a good test for early cancer. It is not sure; it takes too long, and it costs too much ($10,000 for a complete job). But he is cutting down the time and cost. As he collects more records, other startling facts are showing up. For instance, people with hypertension (high blood pressure) generally excrete a special steroid. No one knows why, but Dobriner hopes to find out. The mysterious steroids from the glandular orchestra are apparently concerned with all the changes in the body's cells. "If you want to know about cancer," says Dobriner, "you must also know about old age, hypertension and degeneration." Thus, cancer research may discover, as a sort of byproduct, what makes people grow old.

Human Laboratory. The most important of Sloan-Kettering's laboratories is the great hospital next door, including the Strang Prevention Clinic. Dr. Rulon W. Rawson, head of the Division of Clinical Investigation, explains that, after all, human patients are the best source of information about human cancer. Clinical investigation is a two-way street. Observation of patients, especially their reaction to treatment, gives clues for researchers to follow. When the laboratories develop some new method applicable to human beings, the hospital is the only conclusive place to try it out.

A good example of the interaction of research and clinical study is the work of Rawson's group and of Dr. L. D. Marinelli on the treatment of thyroid cancer with radioactive iodine. Since the thyroid gland eagerly absorbs iodine (which it uses to make a hormone), doctors have hoped that a cancerous thyroid would absorb radioactive iodine 131 in sufficient quantity to kill the unruly cells. Unfortunately, this effort was none too successful. The normal thyroid took up nearly all the iodine. The cancerous thyroid cells, particularly the metastases in distant parts of the body, took up so little that they were hardly damaged by the iodine's radioactivity.

Trained Metastases. Dr. Marinelli and his associates worked out a neat method of dealing with this difficulty. First they removed the patient's normal thyroid and with it the original cancer. This left the metastases which, they found, often consisted of cancer cells that retained faint remnants of the normal function of the thyroid. With the normal thyroid gone, the degenerate cells awoke and began to act like thyroids. Stimulated by the proper drugs, they began taking up iodine and making it into thyroid hormones. Then Dr. Marinelli gave radioactive iodine to the patient. The tumors, acting as pinchhitting thyroid glands, absorbed it readily, and were in some cases destroyed by the iodine's radiation.

Some types of thyroid cancer do not respond to this treatment. The cells cannot be trained to take up iodine and kill themselves. But many patients have been helped to some extent. In four of them the disease has been definitely checked, though not wiped out entirely.

More important, Dr. Rawson believes, is the proof this method gives that cancer cells are not "autonomous"; that in some cases, at least, they can be trained to resume some of the functions of the normal cells from which they are descended. If they can be trained, perhaps they can eventually be trained to destroy themselves.

Dread Decision. The patients in Memorial Hospital are never used as experimental animals. Neither are they denied any treatment, however new, that might possibly do them good. Virtually all patients beyond the help of surgery are willing to have new drugs and treatments tried on them.

In each individual case, the doctors have to make a grim decision. Should they prolong a life that is sure to be "unsatisfactory?" Should they, by prolonging life, place a crushing burden on the patient's family? Should they, in desperate cases when everything else has been tried, use a drug so dangerous that it may kill the patient immediately? Such questions have no single answer. The doctors decide each case separately, considering such matters as the painfulness of the treatment and the patient's chance for happiness during his possible remission.

Some cancer doctors admit that they have almost cracked up thinking about such things, and about their utter helplessness in hundreds of cases. Dr. Rhoads, too, has his moments of depression. He is sure that his method of concerted frontal attack, submerging niceties of scientific temperament, is correct. But he also knows that neither he nor his men nor anyone else in the world has yet found a cancer cure.

Perhaps ... Sloan-Kettering is certainly trying hard. From his office on the 13th floor, Dr. Rhoads can review the work of the world's most impressive array of cancer-fighting weapons: the eggs with their little glass windows, the tubes of cancer tissue on their merry-go-rounds, the rows of deft-fingered girls with the squeaking, doomed white mice, the dangerous viruses, the green and white molds, the thousands upon thousands of chemical agents, the scholarly chemists, physicists, biologists, clinicians all working in unison to defeat the common enemy: cancer.

Perhaps at that moment in Memorial Hospital, a life frayed with pain and dimmed with morphine is flickering down to the cold. Dr. Rhoads is no callous technician. His confident eyes grow sad when he hears of this everyday event. He looks out the window at the cluttered roofs of New York and at a great bridge roaring with traffic. "It needn't be," he says, "not always."

*Asked if she would be afraid of a mouse in her own home, one of the girls replied: "Oh yes. Those are fierce, wild mice."

*This colony of cancer cells, which grew from a single cell in 31 days, has begun to spill out of a tiny glass tube. The cells are magnified about 70 times.

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