Several weeks ago an envious colleague sent John F. Enders, associate Professor of Bacteriology and Immunology at the Medical School, a photograph of Sweden's only lady mayer shown sun-bathing on the beach of her municipality a few miles outside Stockholm. Enders kept it on his desk to remind himself that he had an important engagement with another official of Sweden in Stockholm today.
For this afternoon, research scientist Enders-an unknown figure outside his field will most the King of Sweden and become the seventh member of the Harvard faculty to receive the Noble Prize.
With him will be two associates, co-recipients of the prize, Dr. Thomas H. Weller of the Harvard School of Public Heath, and Dr. Frederick C. Robbins, formerly a research associate in pediatrics at Harvard, now with the Western Reserve Medical School in Cleveland.
Tomorrow, following a banquet given by King Gustav VI for all Noble winners, Enders will deliver before the Swedish Royal Academy of Science the Noble Lecture--written by the three men-and required annually of all winners in the field of science. He will tell how three men in a tiny laboratory at the Children's Hospital followed logical scientific methods to discover the long-sought method of cultivating polio virus in a test-tube. Although their methods were only a slight modification of a research technique first introduced in 1907, they produced a discovery sufficiently significant to inspire the nation-wide Salk Vaccine campaign of 1954.
Moral In Clear
The story behind that discovery might well serve as a modern-day case book in the study of the scientific method. To Enders, the moral is clear: success comes through the persistent use of basic research methods; honor comes only to that research scientist who is only to that research scientist who is fortunate enough to make a final discovery on top of a long string of earlier advancement.
As he said in accepting the Passano Award in 1953 for culturing polio viruses in living tissues:
"I should be especially pleased if I succeed in adding another example to the myriads afforded by the history of science of the general truth expressed so admirably by my former master. Hans Zinsser." And then he went on to quote the colorful professor at the Medical School who wrote in the 1920's "Rats, Lice and History."
"It is an erroneous impression," Zinsser said, " that scientific discovery is often made by inspiration a sort of coup de foudre from on high. This is rarely the case. As a rule the scientist takes off from the manifold observation of his predecessors and shown his intelligence, if any, by his ability to discriminate between the important and the negligible, by selecting here and there the significant stepping stones that will load across the difficulties to new understanding. The one who places the last stone and stops across to the terra firma of accomplished discovery gets all the credit. Only the initiated know and honor those whose patient integrity and devotion to exact observations have made the last stop possible."
Used human Skin
What the trio, under the direction of Enders, had done was select a well-known method of cultivating chicken pox viruses and apply that method to isolating and growing the polio virus. But they had made one important change over previous attempts to grow the virus in a test-tube. It was what Zinsser would have called that last "step across to accomplished discovery." Unlike their predecessors, they had used human skin tissue-instead of nerve tissue-on which to grow the disease. Original as their final step may have been, the three associates regard their success as the by-product of all previous work and research in a field of skin culture that dates at least to 1907.
Nor was their surprise ingenuine when success rather quickly camel in 1948. Enders was to note at a later date. "We were quite surprised and very pleased that it worked." Weller expanded upon the workings of science:
"One doesn't always realize that what one is doing at the time will be successful. In our case, we could hardly believe the results for a while after we had first innoculated the tissue cultures (with polio viruses to get the growing started). And we could not really believes the results until we had conducted extensive tests to gather proof."
"The potentialities of what had happened were, of course, immediately apparent." Enders pointed out. The poliovirus could now be produced in quantity and be sterilized through the method developed to permit mass inoculations the vaccine method was sufficiently developed to permit the mass innoculations against polio last summer.
Prize Followed Others
The Nobel Prize of $28,086 awarded by the Caroline Institute followed on only somewhat less distinguished recognition. In June of 1953, Enders received the Passano, and last tall he was cited for "distinguished achievements in the cultivation of viruses," and given the Lasker Foundation Aware. Finally, last October he was sitting in his office being quizzed over the telephone by the Boston Globe's suspicious science writer, Frances Burns when word first come through that he and his two associated would receive the outstanding science award of the year. "Wait a second," Miss Burns said. "It's coming over the AP wire. You've won the Nobel Prize."
The announcement was the climax but only a temporary one, to a story of three men one each from the Sough, West, and east all of whom came to Harvard to work with its Medical School.
A graduate of St. Paul's School and Yale, Enders took his Ph.D. in Bacteriology at the graduate School of Arts and Sciences during an era, as he says, when "there weren't very many men who took that sort of a degree." In 1930 he won his Doctorate and simultaneously became an instructor in the Department of Bacteriology and Immunology. He had risen to the position of assistant professor by the time he was teaching a young sophomore medical student named Weller in 1937.
Weller and Robbins
Weller had come east from Michigan, where his father is now chairman of the department of Pathology at the University of Michigan Medical School. With him in the class of 1940 was a dark-haired Frederick Robbins from Auburn, Alabama.
In 1946, the Children's Hospital jointed with several other units to form the Children's Medical center, the Board of Trustees created a new division of Laboratories and Research. Enders received and accepted in 1947 an offer to direct one of the units, the Laboratories of Infections Disease Research.
With Weller, who had just finished his residency at Children's Hospital as his assistant, Enders set up the laboratory on the second floor of the old Carnegie Building behind the hospital. Space was so much in demand that they had designate the hallway for their reception room in order to leave space for installing experimental animals. The two then set to work on experiments to cultivate the mumps and inbuenza viruses with which Enders had worked before the War. While in the process of working on these attempts at cultivation, the two decided to try to isolate and grow the polio virus.
"We thought we would make another attempt at growing it," Enders explained later. "There was nothing new about tissue culture of virus, but it seemed to us the possibilities had not been adequately explored. Almost all the virus work had been carried on in susceptible animals like mice, monkeys, and pigs. But scientists had never found it practical. But scientists had never found it practical to work with animals in the case of polio, and nearly all attempts to apply test-tube growth to any kind of virus had failed."
Enders and Weller did know, however, that at least one virus chicken-pox-had bten grown in a test-tube. And the polio virus, was, they noted, similar in many ways to chicken-pox.
They also knew that if they could grow the polio virus in sufficient quantities, it could be neutralized with formaldehyde, and used to produced antibodies--which would combat any polio germs in an inoculated person.
"It seemed worthwhile to try again," Enders reflected, "and amazingly enough what we tried seemed to work!"
Proviously, all attempts at growing the virus has centered around the impractical use of infected monkey brain as culture material. But, as there seemed to be strong evidence that polio grew in the body as well as the brain, the two men decided to try to grow the virus on ordinary human skin cells. This reasoning seemed to be a logical step, especially since the chicken-pox had been grown with human tissue.
"We had a sure way of telling if the virus would grow," Enders pointed out later, "because we found that when it did multiply it killed the living cells of the skin. It is very easy to tell under a microscope whether or not cells are dead."
Taking some "throat washing"-saliva-from a woman infected with polio, they placed it in a test-tube with chopped-up pieces of human skin tissue, then awaited the results, hardly expecting to see any difference occur in the composition of the tissue cells.
But as Enders noted, "We were nevertheless much surprised to find that the virus 'multiplied and was released into the fluid medium in considerable amounts, and indications were obtained that the virus injured and killed the tissue issues."
Next, they needed an indisputable method of demonstrating what they had discovered that the polio virus actually grew in a test-tube.
Here, with Robbins now a member of the team, they explored the "roller tube" method of tissue culture. The simple idea was to place please of tissue in a test-tube with a special nutrient that would make the cells thrive. After observers had clearly established that the tissue cells were thriving on the nutrient tube, Robbins then injected a small amount of polio virus into the tube. To kill the tissue cells, the viruses would have to multiply in their experiments. Invariably, within one to five days the once-thriving tissue destroyed.
The medical research world was con Vinced.
Consult with Salk
Once the viruses could be grown, the doctors conferred with Dr. Jonas Salk of Pittsburgh on the best method of neuralizing the adverse effects of the polio. He exposed the viruses to formal dehyde to destroy their infectivity. His hope and conviction is that they will enable an innoculated body to build up lasting antibodies.
Enders points out that the eventual success of the Salk Vaccine will depend upon how well it can build up antibodies within the central nervous system, as well as in the body itself. "We know the vaccine gets into the blood system, but it has not been absolutely demonstrated that it reaches the nervous system." be said.
Although conclusive evidence of the effectiveness of the Salk Vaccine has not been established, there is not doubt of the success of the enders-Weller-Robbins venture. Repeated evidence shows that the tissue culture method will now be applied to increasingly expanded field of virus research. It was for this wide reaching possibility that Weller and Robbins jointly received the Mead Johnson Award of 1953- for "the development of the tissue culture method will now betion to the field of virus diseases."
No Limits Yet
Nor have Enders and Weller yet reached the limits on research with tissue culture methods. Ender now believes he has isolated the measles virus--by using the same basic process.
"It'snot a very serious disease although though it does produce deaths and harmful secondary effects in parts of the world like Yugoslavia," Enders notes. He is not the least apologetic about taking up a new project of less significance than that of isolating the polio virus. "After all," he notes, "measles are an abominable nuisance."
Final proof of measles virus growth must await Enders" return from Sweden, however. For the 57-year-old research scientist has not yet innoculated monkeys with the test-tube grown measles virus.
Enders has no doubt that animals, It exposed, or innoculated will come down with measles.
In the meantime, today, he must men the King of Sweden and tomorrow must tell the Royal Academy of Science how three Harvard men discovered the "the sue culture' method of growing viruses.