Cornering the Killer
At 8 a.m., a stocky, short-legged man with a brush of steel-grey hair rises from a big breakfast at his Georgian-style house, shoehorns himself into a midget Triumph estate wagon, and drives a couple of miles to the rolling campus of the National Institutes of Health at Bethesda, Md. Parking his small car in the No. 1 reserved spot, Dr. John Roderick Heller Jr. enters an unimpressive building labeled T-19.
Planned to house dogs used in research, the one-story structure is the temporary command post from which Dr. Heller leads the major part of the U.S. fight against one of mankind's oldest and deadliest enemies--cancer. T19 is headquarters of the National Cancer Institute, and John R. Heller, 54, is the National Cancer Institute's director.
Across Dr. Heller's desk, from his far-flung research fields, flow curious and varied intelligence items--students gathering puffball mushrooms, desert rats that have learned to smoke, a drug made from a chemical relative of DDT, a plastic "iron lung'' for mice. To him, they all fit tiny corners of the vast jigsaw that must be filled in before cancer can be conquered. Meanwhile, his reports on the enemy's inroads are grim:
P: Cancer will strike 450,000 Americans this year and kill 260,000, making it the biggest killer after diseases of the heart and arteries.
P: Lung cancer is increasing faster than any other form of cancer, has a lower cure rate than most, will kill 35,000 Americans this year (85% of them men).
P: After increasing alarmingly for a quarter-century, the death rate from leukemia in the North is leveling off, but is still rising rapidly in the South.
Anti-cancer forces have scored some gains, Dr. Heller notes: one cancer victim out of three is now saved, meaning cured or enabled to survive five years or more. Until recently, it was only one in four (see chart). But this advance could be upped by 50% merely by early detection and prompt treatment. About 75,000 cancer deaths every year are needless sacrifices to ignorance, apathy and fear.
To make sure that all cancer victims who can be successfully treated get help, and to find ways of saving the half who are now doomed, NCI, a branch of the U.S. Public Health Service, is mounting history's most intensive campaign against a human illness. Its budget is skyrocketing: from $14 million when Dr. Heller took over in 1948 to $75 million in the fiscal year just ended, to a probable $100 million in the fiscal year just begun. It musters the efforts of 675 direct employees and thousands of independent researchers through grants and contracts. NCI's budget embraces almost 80% of all U.S. outlays for cancer research. Next biggest backer: the American Cancer Society, with $9,250,000 a year.
Nature of the Beast. Research must find answers to three complex questions: 1) What is cancer and what are its causes? 2) How can it best be detected, treated and cured? 3) How can it be prevented?
The experts are in close agreement on what cancer is. First, it is not one disease any more than "infection" is. Cancers ravage the entire plant and animal kingdoms. In man there are 200 to 300 kinds, though 90% of human cancers belong to 30 common types. So "cancer" is a collective term.
The experts are almost unanimous, too, in believing that wherever cancer appears, its essential nature is the same: a growth of cells that have rebelled against the body's rigid chemical control. Normally, hormones and enzymes work together in a delicate harmony of checks and balances to regulate cell growth. Once the cancerous process begins, it tends to snowball. The abnormal cells consume more than their share of cell foods, can flourish in a victim who is starving, or actually cause him to starve. Like juvenile delinquents, they grab what they want, and never grow up to assume the duties of normal, mature cells. They tend to reproduce early and die young.
How do the first abnormal cells get that way? The experts cannot agree. Columbia University's Dr. Samuel Graff expresses the current consensus: all cancerous cells are the result of mutation, and mutations can be set off by many known factors--inherited defective genes, radiation by X or gamma rays, ultraviolet light, many chemicals, including some of the huge class of hydrocarbons, physical irritation of tissues, and certainly in some animal cancers by the invasion of a virus. There may be other, still unknown factors causing mutation.
Villainous Combination. Many people get cancer, but most do not. Are there no mutated cells in the systems of those who escape? Almost certainly there are, says Dr. George Moore, director of New York's Roswell Park Memorial Institute* in Buffalo, biggest of the few cancer research units operated by states. Dr. Moore has studied abnormal cells, which might well be precancerous, in the blood of apparently healthy people of all ages. His thesis: every bird, beast and man produces some such cells at all times, but the body's defenses are usually strong enough to destroy them. That healthy people have a specific immunity against anybody else's cancer has been shown in dramatic tests by investigators from Manhattan's Sloan-Kettering Institute and Ohio State University on prisoner volunteers at Columbus' Ohio Penitentiary (TIME, Feb. 25, 1957)-Victims of advanced cancer have no immunity against their own or somebody else's cancer.
Why and how anti-cancer defenses break down is, in most cases, unknown. Many authorities accept the idea of some hereditary susceptibility. Sometimes there are easy, if superficial, explanations. The combination of a chemical carcinogen (cancer-causing factor) with physical irritation is plainly villainous. Cancer of the scrotum among London chimney sweeps was described by Percivall Pott in 1775. The disease disappeared when the sweeps were taught to wash themselves clean of the carcinogenic soot. Lung cancer from inhaling chromate-ore dusts and nickel-refining fumes can be prevented by the wearing of masks, coupled with adequate ventilation. Even the cancer-causing tobacco-tar fractions isolated by Sloan-Kettering's Ernest L. Wynder (TIME, April 27) seem most potent when their powers are reinforced by irritation or by another chemical--perhaps from automotive or industrial exhausts.
The Hottest Thing. "Right now," says National Cancer Institute's Heller, "the hottest thing in cancer is research on viruses as possible causes." The Rockefeller Institute's Dr. Peyton Rous showed as long ago as 1911 (his findings were unpopular at the time) that one cancer (sarcoma) in chickens is caused and can be transmitted by a virus. Over the years, viruses were found to cause other tumors in birds and lower animals. But the gap between them and man seemed unbridgeable. Then the University of Minnesota's Dr. John J. Bittner showed that breast cancer in certain mice is transmitted by a factor, now accepted as a virus, in mouse mothers' milk. This led to the establishment of mouse "dairies," and the painstaking milking of tens of thousands of rodents. In 1951, Dr. Ludwik Gross of The Bronx Veterans Administration Hospital injected something (evidently a virus material) from leukemic mice into newborn mice, got a high incidence of leukemia and some odd tumors to which little attention was then paid.
Other researchers promptly tried to duplicate Gross's results. One was Dr. Sarah E. Stewart, a tall, vivacious microbiologist turned physician and working in Baltimore for the National Institutes of Health. As so often happens in medical research, she did not get what she was looking for, but she got something better. Many of the mice she injected with Gross's "leukemia virus" got solid tumors, mainly in the parotid (salivary) glands. (Dr. Heller's theory: the Gross material had contained two viruses.) Dr. Stewart teamed with the NIH's Dr. Bernice E. Eddy to grow the solid-tumor virus in tissue cultures of monkey kidney cells (as polio virus is grown to make Salk vaccine).
Vaccination? By now, the SE (for Stewart-Eddy) polyoma (multiple-tumor) virus has hurdled the species barrier and caused cancers not only in mice but in rats and in Syrian and Chinese hamsters. In rabbits, for some strange reason, it causes only benign tumors. So far, Drs. Stewart and Eddy have not been able to infect monkeys with their virus, but a determined effort to do so is under way at Roswell Park Institute. Patricia, a lone baby monkey harboring polyoma virus, has her own spotless nursery where she is cared for by Nurse Althea Higgins. Drs. Stewart and Eddy have gone a vital step farther, treated their virus with rabbit serum, and made a vaccine that protects a big majority of normally susceptible animals against the polyoma virus' effects. At Sloan-Kettering Institute, Dr. Charlotte Friend has cultured a strain of mouse virus that causes leukemia in adult as well as newborn animals, and has perfected a protective vaccine. So in some animals, the circle of evidence is virtually complete: viruses are linked with leukemia and certain tumors, and immunity is offered through vaccination.
The problem: applying these findings to man. At dozens of laboratories in the U.S. and elsewhere, material from human victims of both leukemia and solid tumors is being tested in animals. Some success is reported by Dr. Steven O. Schwartz of Chicago's Hektoen Institute, who has generated leukemia in mice with an extract from the brains of human leukemia victims. At the University of Texas' M. D. Anderson Hospital in Houston, Dr. Leon Dmochowski has taken electron-microscope photographs of what he is confident are virus particles from human leukemia. Other investigators want more proof, but this suggestive evidence helps to close the ring.
Mighty Molecule. The virus theory of cancer causation long seemed to be far out in leftfield, but growing knowledge tends to link it with other anti-cancer plays. Most fundamental of these involves nucleic acids, currently regarded as the secret of life itself (TIME, July 14, 1958). Human cells, tiny as they are, normally contain 46 chromosomes, each containing in turn up to 1,000 molecules of nucleic acid. Each of these molecules, invisible even to the electron microscope under most conditions, is a huge chemical complex embracing tens of thousands of atoms. In mammalian cells the master molecule is one of the thousands of forms of deoxyribonucleic acid (DNA). The vital nucleus of many viruses, especially those causing disease in plants and animals (e.g., cowpox, which gives man immunity against smallpox), is also a form of DNA. Most viruses of human diseases have a nucleus of the slightly simpler ribonucleic acid (RNA). Whether polyoma virus has a heart of DNA or RNA is not yet known.
On how to weave these threads of evidence together there are almost as many theories as researchers. But they converge on this general line: DNA is the master molecule of life, with the power to reproduce itself and also to dictate how chromosomes and entire cells shall reproduce. So an abnormal DNA molecule might not only spawn more abnormal DNA, but also trigger the multiplication of abnormal cells that defy the body's usual chemical regulators--in a word, cancer. A DNA viral nucleus, entering a cell, may substitute part of itself for part of a normal DNA, thus scramble the signals for reproduction given by the master molecule.
To the layman, the most puzzling question remains: If any human cancers are caused by viruses, why have none been clearly identified? (The lowliest of benign tumors, the common wart, is definitely caused by a virus that can cause cancer in animals.) Dr. Eddy explains: "In human disease, it may be that the virus starts the cancerous process, but by the time we detect the tumor, there is so little virus left--or in an altered form--that we cannot detect it." Dr. Stewart sums up: ''Perhaps we just haven't hit upon the right method." To find the right method, National Cancer Institute is doubling its outlays for virus research, through grants to independent investigators, to about $4,500,000 in this fiscal year.
Early Detection. As for detection, treatment and cure of cancer. Dr. Heller sees the most exciting new development in chemotherapy--treatment of the disease with drugs. But before the disease can be attacked, it must be detected, and all too often detection comes too late for treatment to do all that it might.
Probably no man has done more to save lives threatened by cancer than Greek-born Dr. George N. Papanicolaou. 76, of Cornell University Medical College, who devised a test for cancer of the uterus and cervix by smearing mucous secretion on a glass slide and examining the stained cells under a microscope. The "Pap smear" is nc' done routinely in hundreds of U.S. laboratories, for an estimated total of 3.000,000 tests a year--most of them for healthy women wisely having regular examinations. Vast ingenuity has gone into extensions of the Pap test: aerosols to make a smoker cough up deep mucus to reveal lung cancer; swallowed balloons and brushes to catch cells from stomach cancer; special washings to reveal disease in the large bowel and rectum.
Attempts to devise a blood test for cancer (other than "blood cancers" such as leukemia) have been unrewarding, though Sloan-Kettering now has high hopes based on high levels of a substance called cytolipin H in cancer victims' blood. But even if such a test was reliable, it would not tell the cancer's location. Physicians still rely mainly on traditional diagnostic methods: physical examination, visual inspection of accessible sites with such aids as the proctoscope and bronchoscope, Pap smears and X rays.
Knife & Rays. Treatment also is usually traditional: with surgery or X rays. For the most part, cancer specialists have to be content with five-or ten-year survival for their patients, and rate this as a substantial "cure."
Surgery by itself has made such strides that most authorities (including many surgeons) figure that it is nearing the end of the road. Thanks to advances in general surgical techniques and patient care, it is now possible to remove huge masses of tissue, including whole organs and limbs. Hence the grim jest: "They put the specimen to bed and sent the patient to the laboratory." For some cancers there is no doubt that "radical" (meaning drastic and extensive) surgery has pro longed useful life. (The University of Minnesota's famed Heart Surgeon C. Walton Lillehei's most productive years have followed removal of a lymphosarcoma and much related tissue in 1950.)
Almost daily, ways are found to give bigger radiation doses more safely to hard-to-reach parts of the body. Examples: cobalt-60 "bombs," a new cesium-137 unit at M. D. Anderson Hospital, higher-powered X-ray machines and linear-particle accelerators, ingeniously refined ways of implanting radioisotopes such as iridium 192 and yttrium 90 in tumors.
The one essentially new development in cancer treatment is chemotherapy's advance to the point where it gives relief from pain, and usually longer life, to 60% of patients with cancer of the lung, breast, ovary or prostate, as well as leukemia and Hodgkin's disease. From this has come a surge of confidence that increasingly potent drugs can be found that eventually will effect outright cures. So great is this confidence that the Cancer Chemotherapy National Service Center now gets the biggest single bite ($23 million) of NCI's budget, with $18 million going out in grants and contracts for development and screening of new drugs. In addition, almost $4,000,000 goes for testing screened drugs in patients.
From Poison Gases. Chemotherapy, broadly defined, got its biggest boost in 1941, when Chicago's Dr. Charles B. Huggins reported that prostate-cancer victims did better and lived longer after castration. The important thing was not the surgery, but the chemistry--removal of the main source of male sex hormones. Similar but less marked benefits resulted from "chemical castration" by administration of a female hormone. In women, some recurrent breast cancers were retarded by female hormones and others by male hormones. But these treatments relied on natural body chemicals, not synthetic magic.
The transition came in World War. II with nitrogen mustard--synthesized for use as a poison gas. Cancer researchers began testing it. found that it killed cells in rough proportion to their rate of reproduction. Though it killed the cancer cells faster than the normal, it was still highly poisonous, could be given (by intravenous injection) only in small doses. And eventually the cancer cells became resistant to it. History has sadly repeated itself with scores of chemicals of this class (technically "alkylating agents") developed since. About 20 are credited with definite but limited usefulness.
More ingenious than simply poisoning the cancer cell was the idea that it might be fooled into accepting, instead of a normal food substance (metabolite), an analogue (close chemical kin) to fill the metabolite's place but yield no nourishment. First to use antimetabolites this way was Dr. Sidney Farber of Boston Children's Hospital and the Children's Cancer Research Foundation. Knowing that leukemic cells are avid for the vitamin folic acid, he began in 1947 to treat child victims of acute leukemia with analogues of folic acid. Lederle Laboratories sent Dr. Farber two, aminopterin and amethopterin. which soon brought about improvement in most of the children. But after weeks or months, their disease became resistant.
In quick succession came the hormones ACTH and cortisone, which also produced brief remissions in acute leukemia (as in some other cancers of the blood and lymphatic system). Then came another antimetabolite. pioneered by Dr. Joseph H. Burchenal of Memorial Center: 6-mercaptopurine, which interferes with cell nutrition by supplying a counterfeit purine. Physicians treating acute leukemia now ring the changes on these, using one until it loses its effect, then switching to another, sometimes back to the first. No child victims of acute leukemia have yet been saved, but Dr. Farber can report a heartening gain. A dozen years ago, young leukemia patients lived an average of only three or four months, mostly in misery, after their disease was diagnosed. Now the average is at least a year; some live two or three years, and a few still longer. During their remissions the children appear healthy, spend most of their time at home playing happily.
Mice & Men. Inspired by these gains, researchers decided that no bottle on the chemists' shelves should be left unturned. Under the leadership of Director Cornelius P. Rhoads (TIME cover, June 27, 1949), Sloan-Kettering had already begun down-the-line testing, and by nowr has gone through 20,000 compounds. But 100,000 more are available, and as many more can easily be synthesized or extracted from plants, fungi and antibiotic "beers." This was a nationwide job for NCI. Along with a score of private institutes and university laboratories, the chemical and drug industries were enlisted: Brooklyn's Charles Pfizer & Co. is at work under a $1,200,000 contract; Indianapolis' Eli Lilly & Co. does its share at its own expense.
Some 40,000 compounds got preliminary testing last year, with about one in 1,000 showing enough promise to be worth more trials in man, and the rate is expected soon to hit 60,000 a year. First test for every compound involves at least 18 mice, and the consumption of mice is enormous--more than 2,000,000 last year. All must be of pure, inbred strains. One of Rod Heller's worries is that the supply of these precious mice may not keep pace with the demand.
Perhaps the armies of mice and men could be better employed, because the screening tests now used are admittedly crude and unreliable. Not surprisingly, some chemicals that looked good in mice have failed in man, and a couple that missed in the mouse test show promise in man. But better screening methods are being sought, and some researchers believe that they have already found them.
Effective Drugs. Despite admitted drawbacks, chemotherapy has won a solid foothold. Dr. Charles Gordon Zubrod, 45, NCI's clinical director, responsible for all cancer patients treated in NIH's huge Clinical Center (TIME, July 20, 1953), . lists eight forms of the disease that can often be set back by drugs, sometimes for as long as two or three years. These are: acute leukemia in children, chronic lymphocytic and myeloid leukemia in adults, Hodgkin's disease, rhabdomyosarcoma (a rare muscle cancer), Wilms's tumor (in the kidney, present at birth), cancer of the adrenal glands, and choriocarcinoma (mainly in women, and arising from placental material). The list includes four major types of cancer--leukemia, lymphoma. sarcoma and carcinoma. This offers some hope that drugs effective against all the many forms of cancer can be found.
Most gratifying and surprising was the discovery that amethopterin, after years of use in acute leukemia, was effective against choriocarcinoma. Dr. Min Chiu Li, now at Sloan-Kettering, and Dr. Roy Hertz, head of NCI's hormone research, pioneered in this, starting from the fact that the female reproductive tract's cells need unusually large amounts of folic acid. Also important was the fact that women with this cancer excrete abnormally large amounts of a hormone forbiddingly named chorionic gonadotropin, and the progress or arrest of the tumor can be gauged with high accuracy by measuring the quantity of the hormone in the urine. In four years, Dr. Hertz and colleagues have treated 45 women at the Clinical Center, and ten of them now show no sign of cancer either at the original site in the uterus or in the areas to which it had spread. In more than 20 cases, the cancer was slowed for a while but then got out of control. Only one woman showed no benefit.
Extended Powers. The search for anti-cancer drugs is no U.S. monopoly. Several have been developed in Britain. From Japan has come an antibiotic, mitomycin C, with dazzling claims; U.S. researchers grant that it is potent in mice, have been baffled by failure to get good results in man. Soviet scientists are screening chemicals by the carload, and the Chinese Reds --with an eye on the propaganda value in underdoctored Asia--are sifting ancient herbal medicines.
In all, more than 100 drugs are being tested on human patients in 150 U.S. hospitals. Some are taken by mouth; others have to be injected in various ways. Some are used alone, others in conjunction with surgery or radiation. Most provocative is an ingenious technique of Drs. Oscar Creech and Edward T. Krementz, worked out at Tulane University. They isolate the blood flow through a cancerous area with tourniquets, divert it through a heart-lung machine, lace it with some alkylating agent such as nitrogen mustard. The rest of the body is protected against blood-cell destruction caused by the drug, and a far higher dose can be given. Usually, this is an extremity, but with experience the technique is being modified, by its originators and other surgeons, to attack cancers in the shoulder and even the lung or pelvis. Boston's Dr. Farber has found that actinomycin D, a derivative of one of Dr. Selman Waksman's earliest antibiotics, has both anti-cancer activity of its own and the power to increase the effectiveness of X rays. So now he uses both in a double-barreled blast against certain children's cancers.
Prevention. From all these varied approaches, Dr. Heller is confident, drug treatment will emerge as the equivalent of surgery and radiation, with its powers extended from palliation to actual cure of cancer.
Obviously, the ultimate goal is prevention. Here cancer offers its usual paradoxes. There is no faintest clue as to how most of the commonest forms can be prevented; yet in those cases where trigger mechanisms have been spotted, preventive measures have been more effective than against any other disease. Scrotum cancer of U.S. oil workers, from a wax-pressing process, has been wiped out (as was chimney sweeps' cancer) by keeping the dangerous chemical at a distance. So has bladder cancer in the dye industry. Circumcision and scrupulous cleanliness markedly reduce a man's risk of cancer of the penis, and possibly his wife's risk of cervical cancer.
Biggest question in prevention today is how the rise in lung cancer--virtually confined to heavy-smoking men--can be checked and reversed. Rod Heller, bureaucrat and son of a tobacco-growing state (although he has never smoked), has weighed all the conflicting evidence and arrived at a forthright conclusion: "Statistical evidence, supported by laboratory findings, has shown that excessive cigarette smoking can be a cause of lung cancer, and that the greater the consumption of cigarettes, the greater the risk." Practical Dr. Heller sees little prospect of changing U.S. smoking habits, pins his hopes for lung-cancer prevention on con victing a specific substance in tobacco tars as the guilty agent, then getting rid of it.
Firsthand Experience. The field of cancer is so vast, so full of unexplainable contradictions, so stubborn in resisting a decisive, exploitable breakthrough, that the army of investigators deployed in it suffer more frustration than most men on medicine's frontiers. The emotional anguish inseparable from cancer heightens their tension. The result is more than average jealousy and backbiting among cancer fighters. As chief coordinator in this setting, Rod Heller is a near ideal choice. Says a leading independent cancer specialist: "He doesn't make people mad. He's a diplomat." Says Heller himself: "You could call me a reasonably relaxed person."
Born at what he calls a "wide place in the road" named Fair Play, S.C. (40 miles southwest of Greenville), Heller is the son and grandson of physicians, had a brother and an uncle with M.D.s. Yet when he entered Clemson College at 16, Rod went into engineering. He switched to the family tradition in time to get his M.D. from Atlanta's Emory University in 1929. Joining up with the U.S. Public Health Service in 1931, he began hopscotching around on two-year tours of anti-VD duty. In 1934 Dr. Heller married Susie May Ayres, daughter of a Tennessee banker. John Roderick III was born to the traveling Hellers in Harrisburg, Pa., second son Hanes in New Orleans, third son Winder (rhymes with finder) in Washington. At least one should keep the M.D. line going: Hanes, 19, is a pre-med student at Yale.
Though NCI was set up in 1937, it never really got rolling until after World War II. Meanwhile, Dr. Heller had become chief of the PHS's VD division, set up rapid-treatment centers around the country. Thanks to these and penicillin, says Heller, "I worked myself out of a job." In 1948 he got the top spot at NCI, but not until 1956 did cancer become a personal matter to him. Then a small growth (basal cell carcinoma) developed at the base of his left nostril. It was removed surgically, and Cancer Fighter Heller rates himself a cured cancer victim.
His relaxed style enables Heller to handle a hodgepodge of administrative duties, keep a balance between jealous scientific factions, attend countless cancer congresses (he was in Lima and Bogota last month, is in Denver this week), and handle touchy appropriations questions with congressional committees. Dr. Heller is opposed to a "crash program," often advocated by laymen with the Manhattan Project in mind. There is, he says, not enough fundamental information available to base it on. But he insists: "With an accelerated and orderly effort to find the answers to cancer, we are going to get them. You can't use all the resources of this country--all the things that have conquered worlds--without something giving. If we could find just one cause of one cancer, and show how it operates, we would have our foot in the door of mankind's most terrible killer. I am confident that we will have some success in the next few years."
*Named for no greensward, but for Surgeon Roswell Park (1852-1914), who announced in 1897 that cancer was probably caused by "infective particles," decided that in two years they could be pinpointed, and that a cure could be found if he had an appropriation of $10,000. He found the money but no cure.
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