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Medicine: Closing in on Polio

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In northern India’s state of Uttar Pradesh last week, Moslem trappers working in teams of four set out their nets before dawn. While three hid, one man walked to a clump .of trees. Loudly he called “Ao! ao! ao!” (Come! come! come!), and began to scatter grain. Rhesus monkeys scrambled down and followed his grain trail. When the monkeys got to the grain in the trap, a hidden operator pulled a cord and meshed them in the netting, an average dozen at a time.

The Moslems (no Hindu will do this work because of religious scruples) stuffed the monkeys into bamboo cages and carried them on shoulder poles into Lucknow. The train hauled them 260 miles to New Delhi. There, 1,000 specimens carefully chosen for health and size (4 to 8 Ibs. apiece) were collected. Then a four-engine transport flew them, with a full-time attendant to feed and water them three times a day, the 4,000 miles to London. Next, another plane and another attendant took them 3,000 miles to New York’s Idlewild Airport and trucks carried them 700 miles to Okatie Farms in South Carolina. There the rhesus monkeys from India were caged with other hordes of “Java” (Cynomolgus) monkeys from the Philippines, to be used as ammunition in a great battle now being fought by medical science. The enemy: polio.

Though Okatie Farms may receive 5,000 or more monkeys a month, the supply never catches up with the demand. After 21 days for rigorous health checks, they are on their way to laboratories in Toronto, Pittsburgh, Detroit and Berkeley, Calif.

From South to North. The man behind most of this monkey business (the biggest in history) is Jonas Edward Salk, 39, an intense, single-minded medical researcher who spends his days and a large part of his nights in the University of Pittsburgh’s Virus Research Laboratory. Behind Salk. in turn, are Si million of the 3 billion dimes that the U.S. public has given to the National Foundation for Infantile Paralysis.

This spring. Dr. Salk’s vision and his delicate laboratory procedures and logarithmic calculations are to be put to the test. Beginning next month in the South and working North ahead of the polio season, the vaccine that Salk has devised and concocted will be shot into the arms of 500,000 to 1.000,000 youngsters in the first, second and third grades in nearly 200 chosen test areas. A few months after the 1954 polio season is over, statisticians will dredge from a mountain of records an answer to the question: Does the Salk vaccine give effective protection against polio?

Dr. Salk’s laboratories could not produce more than a fraction of the hundreds of gallons of vaccine needed for such a massive trial. So it is being made according to his specifications on a nonprofit basis by five pharmaceutical houses—Parke, Davis & Co. in Detroit. Pitman-Moore and Eli Lilly & Co. in Indianapolis, Wyeth Inc. in Philadelphia, the Cutter Laboratories in Berkeley, Calif. For all of them, the indispensable raw material is the monkey, and the procedure is much the same. For example:

The University of Toronto’s Connaught

Medical Research Laboratories use 60 to 65 monkeys in a single morning. Each is deeply anesthetized with ether. In a couple of minutes a skilled surgeon removes the kidneys. Then the monkey is killed with an overdose of ether. Patient technicians cut the kidneys into tiny pieces with nail scissors. The bits of tissue go into big glass bottles with a pink solution known by its formula designation: No. 199. Hundreds of bottles are rocked gently for six days in an incubator, and kidney cells grow in the fluid as though they were still in the living animal.

In a room with the safety rules and precautions of a radioisotope laboratory, 2 cc. of fluid containing live polio virus are added as a seed stock to each quart of tissue fluid. Back to the rocker go the bottles. The virus multiplies a thousandfold in the kidney cells, and after about four days the potentially deadly crop is ready for harvest. It is chilled in 2½gal. bottles for trucking from Toronto to Eli Lilly & Co. and to Parke, Davis.

Mixing the Vaccine. In a rambling pharmaceutical plant beside the Detroit River, the Parke. Davis technicians perform more alchemy. Using both Toronto-grown virus and their own crop, they filter the brew (to get rid of kidney cells, which might cause nephritis), make up 12½-gal. lots in steel tanks and add a dilute formaldehyde solution. When they are satisfied that the formaldehyde has killed every one of the billions of virus particles in the tank, they are ready to mix the vaccine.

So far, each step has been taken with only one type of polio virus present. But the hundreds of strains or varieties of polio virus are classified in three major types, any one of which can cause disease. So one strain of each of the three basic types must be in the vaccine. Dr. Salk’s prescription calls for the Mahoney strain (Type I), MEF-I strain (Type II) and the Saukett strain* (Type III). Three tankfuls, each containing one type of virus in its inactivated state, are mixed. The formaldehyde is neutralized with sodium bisulfite.

Then begins a painstaking, month-long process of testing, with more tissue cultures and inoculations into live monkeys, rabbits, guinea pigs and mice to make sure that the vaccine is safe to inject into humans. These tests are made simultaneously on each batch of vaccine by the manufacturer, by Dr. Salk’s laboratories and by the National Institutes of Health at Bethesda, Md.

Like Cherry Soda. Finally passed and put up in little glass bottles, the vaccine is a clear solution the color of cherry soda. But few children will have time to notice this resemblance. In a typical vaccination program at Colfax School in Pittsburgh, jabbering youngsters trooped by classes to the kindergarten room where Dr. Salk’s assistants had set up desks and chairs beside tables loaded with labeled test tubes, vaccine bottles and stacks of hypodermic needles.

As each child entered the room, Dr. Salk’s secretary handed him a test tube bearing the youngster’s name and control numbers. Time and again, in answer to an anxious “Wotta they gonna do?” she explained the procedure softly and reassuringly. Working in twos, nurses slipped a needle into a vein in the hollow of the child’s elbow (what doctors call the antecubital fossa) and snapped a vacuum seal. Immediately the tube began to fill with blood. Most of the youngsters watched with impersonal detachment, and girls were no more upset by the sight of blood than boys. (These blood samples will be tested to see how many children already had antibodies to one or another type of polio virus. In the forthcoming national trials, no more than 10% of the children will be asked to give blood for a cross-section sampling.)

The child’s other arm was promptly swabbed with alcohol and Dr. Salk hustled over with a hypodermic. Though the syringe might hold up to 5 cc. of vaccine, the needle was changed for each child to cut down the danger of serum hepatitis. With a quick, deft motion perfected by much practice, Dr. Salk jabbed the needle in and pushed the plunger until 1cc. had been injected. Most children let out an “Oh!” or “Ow!” and marched off, self-consciously proud, to another room where a nurse watched their reactions. One of the commonest: “Why. I didn’t even cry!”

Nearly every child got a warm smile and a word of encouragement from Dr. Salk, who obviously enjoys working with them. Some who were yelling with fright he calmed easily. He waved along the few who could not be pacified—he would rather miss an injection than give one to a hysterical child.

Consenting Parents. By 1953’s end, Dr. Salk had given his vaccine to about 1,000 children and adults in communities around Pittsburgh, with good evidence of an increase in antibodies and no bad reactions. Many doctors, especially state and county health officers who must take responsibility for the trials in their areas, argued that 1,000 cases were not enough to prove the safety of the vaccine or give a valid indication of its effectiveness. They suggested advance trials of 10,000 and 50,000 subjects. This would have meant a full year’s delay of the large-scale national trials.

To meet these objections, Dr. Salk has had a busy season of needlework. In little more than five weeks he has inoculated almost 5,000 children in. the Pittsburgh area. Some have had three shots, some two, some one, all with vaccine made in his own laboratory. Now Dr. Salk has begun a marathon vaccinating program. Switching to commercial vaccine, he will try to inoculate 2,500 children this week and finish their quota of shots in time for the foundation to begin mass trials in the South about April 12. By then, enough commercial vaccine will be ready for 370,000 children, foundation officials have computed, and there is plenty more coming along in the pipeline.

This week, though some state officials were giving only guarded, conditional permission for the trials, there was no doubt of the public’s eagerness to see the vaccine tested, or of its faith in the mystical powers of white-coated medical researchers to exorcise the demon polio that has made each summertime a season of fear. In Pittsburgh schools, 80% to 95% of parents with children in the first three grades gave written consent for the vaccinations, and nearly all these youngsters showed up on V-day.

Among the 1.000,000 children that the foundation hopes to vaccinate there would be (by recent U.S. averages) 700 cases of detectable polio this summer. Of these. 483 would, sooner or later, recover completely, 175 would have some permanent paralysis and 42 would die. The value of Dr. Salk’s vaccine will be measured by the extent to which it cuts the number of paralytic cases.

Endemic & Epidemic. It is still too early to answer the question, “Is this the year of victory over polio?” But there is good reason to believe that the Salk vaccine, or one of several on which work is proceeding in other laboratories, will give effective protection against the disease. This assurance lies in the body of knowledge, already immense and now growing faster than ever, that scientists have accumulated about polio. Most of this knowledge has been gained in the last 15 years by researchers working with grants from the National Foundation. It has taken so long because polio is full of paradoxes.

Tireless work by such researchers as Dr. William McD. Hammon of gamma globulin fame (TIME, Nov. 3, 1952) and Yale’s Dr. John R. Paul shows that polio is a worldwide, natural infection of man and at least as old as civilization. And the first and greatest paradox is that the more widespread the infection, the less disease there is.

Infantile paralysis was noted as uncommon but regular and widespread (and therefore endemic) by Britain’s Dr. Michael Underwood in 1784. Sweden had the first reported epidemic of polio in 1887. Seven years later came the first U.S. epidemic, in Vermont’s Otter Creek Valley. Around Rutland and Proctor there was no fewer than 119 paralytic cases. By brilliant horse & buggy epidemiology, Dr. Charles S. Caverly concluded that the old endemic infantile paralysis and the new epidemic polio were one and the same disease.

Bit by bit it became clear that polio is caused by a virus, the “ultimate parasite” of nature that can multiply only within living cells of a higher order—and is too small to be seen by any pre-electronic microscope. Unlike most other disease-causing microbes, this virus does its damage only by attacking the central nervous system,* paralyzing nerve centers and pathways that control distant muscles. Nerves governing the legs, arms and breathing are particularly susceptible. In the severest and commonly fatal bulbar cases (involving the bulb at the base of the brain), speech and swallowing are affected as well as central breathing control.

“We Have Had It.” The second great paradox of polio follows naturally from the first: as a disabling disease, it is a product of civilized man’s passion for sanitation, sewerage and other public-health measures. While other infectious diseases have decreased with higher living standards, paralytic polio has been increasing. Man himself is the only known natural reservoir of the virus. How it reaches him and enters his system is not known for certain, but the current consensus is: person to person, rather than by pests (though flies can carry the virus), and through the mouth. It may be hand to mouth, or by inhalation, or both.

For a few days the virus courses through the bloodstream—one of the most vital recent discoveries, made simultaneously by Baltimore’s Dr. David Bodian and Yale’s Dr. Dorothy Horstmann. While there, it stimulates the human system to develop antibodies that will give some degree of immunity -against future infection by virus of the same type but not to any appreciable degree against virus of the two other known types.

The virus multiplies somewhere along the digestive tract and is excreted from the intestines. In unsanitary societies, everybody is soon exposed to the virus. If the challenge of infection comes in earliest infancy, that is good. For if the mother has been exposed and has antibodies, she passes them on to her baby. They stay in the baby’s bloodstream, giving “passive immunity” (TIME, Nov. 5, 1951) for about three months. Exposure to the virus during that time usually causes no detectable symptoms, but results in lifelong, active immunity.

As man has lifted himself slowly out of his own filth, he has reduced the likelihood that a child will be exposed to a virus that is mostly flushed down the drain. And the later the age of exposure, the greater is the danger that the infection will develop into a grave, feverish and perhaps paralytic illness. The reason why most of the populace seems to be immune, says Dr. Paul, is simply: “We have had it.” But without knowing it. As U.S. standards of hygiene have gone up, so has the age range in which paralytic polio strikes. Nowadays. 22% of victims are adults. Strangely, the disease attacks more boys than girls under 20, but more women than men over 20.

The Great Breakthrough. Five years ago came the great breakthrough in the campaign to conquer polio. There had already been ill-starred attempts to make a vaccine, but in everything that they tried to do the researchers were hampered by one stubborn fact: most kinds of polio virus, it seemed, could be grown only in nerve tissues of living men or monkeys. And a vaccine prepared from such material would hold the frightful danger of causing an allergic inflammation of the brain, a malady even worse than the one it was designed to prevent.

A team of Harvard researchers headed by the brilliant virologist, John F. Enders, reported in Science in January 1949 that they had succeeded in growing polio viruses in tissue cultures of non-nervous tissues. From the obscure technical lan guage they used, only another virologist could have divined the explosive import of their work. In fact, Enders’ discovery was to a polio vaccine (and to much other health-saving virus research) what Einstein’s cryptic E = mc2 was to the atom bomb.

The expression “tissue culture” is a sleeper. It means taking pieces of human or animal tissue and keeping them alive in a nourishing solution so that new cells grow in the test tube. After trying a variety of human tissues, Dr. Enders and other investigators hit upon the kidney of the rhesus monkey as a readily available material in which viruses could be mass-produced. At last researchers had a safe starting material for a vaccine. Moreover, tissue cultures could be used to find out something at which immunologists pre1viously could only guess: how high a level of antibodies a person must have to enjoy immunity against polio.

The Knowns & Unknowns. This was where Dr. Salk came in. Born in Manhattan in 1914. eldest of three sons-of a women’s-wear manufacturer. Jonas Salk was a precocious youngster with unusually neat and tidy habits and eaually precise ways of classifying ideas. He graduated from Townsend Harris High School (for “accelerated” students) at 16 and from the College of the City of New York at 19. After his freshman year at New York University Medical School. Jonas Salk was already so interested in research that he took a year out to work on protein chemistry. Asked today why he devotes his life to research. Salk counters: “Why did Mozart compose music?”

The research bug was in his blood, and to stay. After a Manhattan internship, the eager Dr. Salk did not even consider going into routine practice. Instead, he won a National Research Council fellowship for work on viruses. One of his favorite N.Y.U. professors. Dr. Thomas Francis Jr., had gone to Ann Arbor, and there Salk joined him. He was there in 1947 when Dr. William Swindler McEllroy, the University of Pittsburgh’s dean of medicine, was looking for a bright young man to start a virus laboratory. Dr. McEllroy had always wanted to do virus research himself, and this, he figured, was the time to get cracking, since the antibiotics were beating the daylights out of most of the bacterial infections. In Salk he saw both a promising virologist and a man to fulfill his own dreams.

With his wife, the former Donna Lindsay of Manhattan, and two young sons (there is a third now), Dr. Salk went to Pittsburgh on faith. There was no virus laboratory and only enough personnel for a skeleton staff. But Dr. McEllroy got him space in the basement of the misnamed Municipal Hospital, little used because it is limited to a few infectious diseases and is half-empty after the polio season. (Epidemiologist Hammon now occupies fourth-floor quarters in the same building.)

A quick and logical thinker and a quick, incisive speaker. Dr. Salk plunged into his work with boundless energy. At the beginning he stuck to his first love, the influenza viruses. But soon he decided to “look into this polio problem to see what it was about.” The time was exactly ripe for a man with a passion for plotting knowns and unknowns in schematic dia gram and an ability to stick to it day and night.

It is not unusual for him to work a 16-hour day six days a week, though he tries to take most of Sunday off to be with his boys. Golf and tennis are only memories nowadays. Typical of Dr. Salk’s concentration, and an example of his humor, is a story told by Mrs. Salk. She was talking to him about family matters and could tell by his faraway look that his thoughts were back in the lab. “Why, Jonas,” she protested, “you’re not listening to me at all.” Grinned Dr. Salk: “My dear, I’m giving you my undevoted attention.”

Medium No. 199. Salk’s first chance to make a name for himself in polio work came in 1949. Baltimore’s Dr. Bodian and Dr. Howard Howe had concluded that all known strains of polio virus belonged to three types, as far as immunity was concerned. If this were true, one strain of each would have to go into a vaccine, and no more. How to be sure? The National Foundation commissioned four university laboratories, including Dr. Salk’s, to classify 100 strains. The task took three years, cost $1,370,000. Salk and his associates typed 74 strains. Along the way, Salk became a devotee of Enders’ tissue culture technique (some “older and wiser” polio researchers missed the boat by neglecting this), and characteristically, he sought ways to improve it.

Dr. Salk set his growing staff to testing different parts of the monkey’s anatomy to find the most useful virus-growing tissues. Like Enders, they found the kidney the best. But a question that Enders and his colleagues had not settled was the best broth in which to grow the tissue cells. Dr. Salk tested many, picked Medium No. 199, containing 62 carefully balanced ingredients, from common salt to penicillin, which Toronto’s Dr. Raymond C. Parker had developed for culturing cancer cells.

It did not take Dr. Salk long to see that ready at hand were all the essentials needed, at least in theory, to make an effective polio vaccine: plenty of virus, grown safely in non-nervous tissue; convincing evidence that only three types of virus need be in the vaccine; means to kill or inactivate the virus and still leave it with the power to stimulate the human system to produce protective antibodies. The best way to kill the virus with formaldehyde solution was not known, but Dr. Salk tried dozens of different concentrations and temperatures. “When you try 30 variables,” he says, “you’re sure to hit the right one.” Also unknown was the level, or titer, of antibodies a person must have to enjoy protection against polio.The Hurry-Up. Step by painstaking step, Dr. Salk made experimental vaccines and tested them in monkeys. In June 1952 he was satisfied that he had a vaccine safe enough to be given to human beings. Still, for utmost safety, he decided that the first subjects should be those who had already recovered from polio. Thus they should be immune to further disease, but he could measure a rise in their antibody level if the vac cine produced, as he expected, a booste effect. It did.

A year ago this week, Dr. Salk described his encouraging results in a nationwide CBS broadcast titled “The Scientist Speaks for Himself.” Fellow scientists mistook his motives and criticized him for not confining his reports to professiona! journals. And they have kept on criticizing him ever since, softly in public but loudly in private, for being a young man in a hurry. In his files are masses of data to support the conclusions he has announced. But Dr. Salk has not taken the time to work up more than a fraction of these data for publication. A cautious Yankee with long years of experience with viruses and vaccines objects: “We want Salk to show us, not tell us.”

However, the haste to put on the mass-inoculation trials this year originates in the National Foundation. Its President Basil O’Connor, onetime law partner of history’s most famed polio victim, Franklin D. Roosevelt, argues that the foundation has as great an obligation not to delay unduly the use of a serviceable vaccine as it has not to rush one to trial too soon. But the hurry-up has caused plenty of trouble within the foundation. It was partly responsible for the fact that Dr. Harry Weaver, a human dynamo who had directed its research program for seven years and worked out the “monkey airlift,” left last summer. Along with disagreement over technical details, it was to blame for the walkout by Dr. Joseph A. Bell, after he had taken leave from the Public Health Service to supervise the trials for the foundation.

The Assured Gamble. Now the foundation has played an ace. It has persuaded Dr. Francis to evaluate the results of the trial. He is no man to be influenced by foundation pressure or fondness for his protege, Dr. Salk. And he dictated the terms before he took the job. So instead of the foundation’s original plan to vaccinate all second-grade youngsters in a test area and leave the first-and third-graders unvaccinated as controls, twelve states will have a more precisely controlled setup. Children in the first three grades will be inoculated, but half will get the vaccine and half an inert liquid or placebo. And nobody will know—until Dr. Francis and his assistants at Ann Arbor decode the numbers—who got which.

Whatever is done this year, many polio experts will not be satisfied. Some do not believe that a killed-virus vaccine can be as effective as one made from live virus that has been “attenuated” or adapted so that it has lost its power to cause disease. Prominent among these is Cincinnati’s Dr. Albert Sabin, who believes he is well on the way to producing such strains of virus and also has hopes of finding them in nature. A killed vaccine, he argues, may give immunity for only a year or a few years, so repeated shots would be needed, whereas a live vaccine is more likely to give lifelong immunity.

At Chicago’s Michael Reese Hospital, Drs. Albert Milzer and Sidney Levinson have developed a vaccine similar to Salk’s except that the virus is killed by ultraviolet radiation. This, they believe, does less damage to the virus particles than formaldehyde, and so produces a more potent vaccine. So far, they have inoculated 30 volunteers, with no ill effects and with good antibody response. But they would not be ready for a mass trial of their vaccine for another year.

Some critics object to Salk’s use of the Mahoney-(Type I) strain of virus because if any live particles slipped through they could cause severe paralysis after injection into muscle. Dr. Salk answers that if no live particles can get through, it cannot matter what they might do. And he makes sure, by the most rigorous testing that he has been able to devise, that every virus particle is killed. ^ Dr. Salk has had no unfavorable reactions with his vaccine. On the evidence to date, there is no reason for parents to withhold permission for their children to take the shots soon to be offered. If any unfavorable reactions develop, they are likely to be minor, and if serious, as rare as the one case in 10,000 that reacts badly to diphtheria vaccine. A verdict on the effectiveness of the Salk vaccine, for a single polio season, must await Dr. Francis’ report a year from now. Dr. Salk has high hope that his vaccine will lead the way to lifelong immunity; proof of this will take more years.

‘This year’s mass trials are the greatest gamble in medical history,” says a polio researcher, who, admittedly, favors a live-virus vaccine. But the gamble is sure to pay off one way or another. If the Salk vaccine is effective for even one season, 1954 will be a year of signal victory against polio; if it is not, little will have 3een lost and much knowledge gained for a new attack.

-Isolated in Dr. Salk’s laboratories from James Sarkett, now 14, when he had paralytic polio four years ago. His name was not clear on the specimen bottle and a researcher misread it as “Saukett.” In this form it is now perpetuated, beyond hope of correction, in countless scientific publications. -Hence the name, poliomyelitis—literally, inflammation of the grey marrow (part of the spinal cord). -Both his brothers chose careers on the borders of medicine. Herman. 34, is a veterinarian in Mars, Pa. Lee, 27, is a candidate for a Ph.D.

in clinical psychology at the University of Michigan. -Instead of the famed old Brunhilde strain (named for a chimpanzee used in polio research at Johns Hopkins).

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