If pigeons could be immunized, humans likely could be too. As they had with cholera, French and German scientists raced each other, building upon Sewall's and each other's advances, studying both diphtheria and tetanus. In December 1890, Koch protegés Emil Behring, who would later win the Nobel Prize, and Shibasaburo Kitasato showed that serum (the fluid left after all solids are removed from blood (drawn from one animal made immune to tetanus could be injected into a different animal and protect it from disease.
The paper shook the scientific world. Work on diphtheria at a level of intensity heretofore unknown proceeded in laboratories. Over the Christmas holiday in 1891 in Berlin, the first attempt to cure a person of diphtheria was made. It succeeded.
Scientists had discovered a way not simply to prevent a disease. They had found a way to cure disease. It was the first cure.
Over the next few years work continued. In 1894, Emile Roux of the Pasteur Institute read his paper summarizing experiments with diphtheria antitoxin before the International Congress on Hygiene in Budapest.
Many of the greatest scientists in the world sat in the audience. As Roux finished, these men, each renowned in his own right, began to clap, then stood on their seats, their hands making thunderous sounds, their voices shouting applause in half a dozen languages, their hats thrown to the ceiling. Welch then reported American experiences confirming the work of both the French and Germans. And each delegate returned to his home with a bottle of this marvelous curative agent in his possession.
*
In the keynote speech at the next meeting of the Association of American Physicians, an association created to foster scientific medicine, Welch said, 'The discovery of the healing serum is entirely the result of laboratory work. In no sense was the discovery an accidental one. Every step leading to it can be traced, and every step was taken with a definite purpose and to solve a definite problem. These studies and resulting discoveries mark an epoch in the history of medicine.'
His comment was a declaration not of war but of victory. Scientific medicine had developed technologies that could both prevent and cure diseases that had previously killed in huge numbers, and killed gruesomely.
And if French and German scientists had found the antitoxin, Americans William Park, chief of the laboratory division of the New York City Health Department, and Anna Williams, his deputy and perhaps the leading female bacteriologist in this country (possibly anywhere (transformed it into something that every doctor in the developed world had easy access to. They were an odd couple: he with an original and creative mind but staid, even stolid, extremely precise and well organized; she, wild, risk taking, intensely curious, a woman who took new inventions apart to see how they worked. They complemented each other perfectly.
In 1894 they discovered a way to make a toxin five hundred times as potent as that used by Europeans. This lethality made a far more efficient stimulator of antitoxin and slashed the cost to one-tenth what it had been. Park then broke the production process into tasks that ordinary workers, not scientists, could perform and turned part of the laboratory into a virtual factory. It soon became by far the cheapest, most efficient, and reliable producer of the antitoxin in the world. Diphtheria-antitoxin production today is still based on their methods.
The lab distributed it free in New York and sold it elsewhere. Park used the money to subsidize basic research and make the city laboratories into arguably the best medical research institution in the country at the time. Its annual reports soon contained, according to one historian of medicine, 'a body of research of which any Institute in the world would be proud.'
And the antitoxin suddenly became available around the world. Diphtheria fatality rates quickly fell by almost two-thirds, and country doctors began to perform miracles. It was only the first miracle of what promised to be many.
*
As the use of this antitoxin was becoming widespread, Frederick Gates, an intellectually curious Baptist minister who had a gift for seeing opportunities to exploit and was an assistant to John D. Rockefeller, picked up a medical textbook written by William Osler called The Principles and Practice of Medicine, a textbook that would go through many editions and find a readership among both physicians and informed laymen. In it Osler traced the evolution of medical ideas, explored controversies, and, most significantly, admitted uncertainty and ignorance.
Gates had started working for Rockefeller as a philanthropic adviser, but nothing limited him to eleemosynary concerns. He organized several Rockefeller business ventures, pulling, for example, a $50 million profit out of the Mesabi iron range in Minnesota. Rockefeller himself used a homeopathic physician, and Gates had also read The New Testament of Homeopathic Medicine, written by Samuel Hahnemann, founder of the movement. Gates decided that Hahnemann 'must have been, to speak charitably, little less than lunatic.'
Osler's book impressed Gates in very different ways for it presented a paradox. First, it showed that medical science had immense promise. But it also showed that that promise was far from being realized. 'It became clear to me that medicine could hardly hope to become a science,' Gates explained, 'until' qualified men could give themselves to uninterrupted study and investigation, on ample salary, entirely independent of practice' . Here was an opportunity, to me the greatest, which the world could afford, for Mr. Rockefeller to become a pioneer.'
Meanwhile, John D. Rockefeller Jr. talked about the idea of funding medical research with two prominent physicians, L. Emmett Holt and Christian Herter, both former students of Welch. Both eagerly endorsed the idea.
On January 2, 1901, Rockefeller Sr.'s grandchild John Rockefeller McCormick, also the grandchild of Cyrus McCormick, died of scarlet fever in Chicago.
Later that year the Rockefeller Institute for Medical Research was incorporated. It would change everything.
*
Welch declined the offer to head the new institute but he assumed all the duties of launching it, chairing both the institute board itself and its board of scientific directors. That scientific board included Welch's old friend T. Mitchell Prudden, Holt, Herter, two other prominent scientists who had been students of Welch, and Harvard's Theobald Smith. Smith, one of the leading bacteriologists in the world, had been Welch's first choice for director but had declined because he had done most of his research on animal diseases (for example, developing a vaccine to prevent hog cholera (and thought it would be more politic to have a director who had investigated human disease.
So Welch offered the position to Simon Flexner, who had left the Hopkins to take a highly prestigious professorship at the University of Pennsylvania's medical school. (Flexner had rejected an offer of an $8,000 salary from Cornell to take the position at Penn at $5,000.) But his appointment had been contentious, and at the meeting where he was chosen one faculty member said that accepting the Jew as a professor did not involve accepting him as a man. Daily he fought with other faculty over both personal and substantive issues.
Flexner accepted Welch's offer, and a raise. But the launching of the institute remained firmly under Welch's control. In this, Flexner said, Welch 'accepted no assistance, not even clerical. Every detail was attended to with his own hand, every letter handwritten.'
The European research institutes were either dedicated to infectious disease or designed to allow freedom to individuals such as Pasteur, Koch, and Ehrlich. The Rockefeller Institute saw medicine itself as its field; from its earliest existence, scientists there studied infectious disease, but they also laid the groundwork in surgery for organ transplants, established links between viruses and cancer, and developed a method to store blood.
At first the institute gave modest grants to scientists elsewhere, but in 1903 it opened its own laboratory, in 1910 its own hospital. And Flexner began to come into his own.
*
There was a roughness about Simon Flexner, something left over from the streets, from his growing up the black sheep in an immigrant Jewish family in Louisville, Kentucky. Older and
younger brothers were brilliant students, but he quit school in the sixth grade. Sullen and flirting with delinquency, he was fired even by an uncle from a menial job in a photography studio. Next he worked for a dry-goods dealer who defrauded people and fled the city. A druggist fired him. His father gave him a tour of the city jail to try to frighten him into obedience, then arranged a plumbing apprenticeship, but the plumber balked when Simon's old principal warned him 'not to have anything to do with Simon Flexner.'
At the age of nineteen Flexner got another job with a druggist, washing bottles. The shop had a microscope and the druggist forbade him to touch it. He ignored the order. Flexner hated any kind of tedium, and taking orders. What the microscope showed him was not at all tedious.
Abruptly his mind engaged. He was fascinated. He began making sudden impossible leaps. In a single year he finished a two-year program at the Louisville College of Pharmacy and won the gold medal for best student. He began working for his older brother Jacob, another druggist who also had a microscope; now Simon did not have sneak to use it. Simultaneously he went to a medical school (at night. Flexner later recalled, 'I never made a physical examination. I never heard a heart or lung sound.'
But he did get an M.D. His younger brother Abraham had graduated from the Hopkins, and Simon sent some of his microscopic observations to Welch. Soon Simon was studying at the Hopkins himself.
Welch took to him though they were opposites. Flexner was small and wiry, almost wizened, and no one ever called him charming. He had an edgy insecurity and said, 'I have never been educated in any branch of learning. There are great gaps in my knowledge.' To fill the gaps, he read. 'He read,' his brother Abraham said, 'as he ate.' He devoured books, read everything, read omnivorously, from English literature to Huxley and Darwin. He felt he had to learn. His insecurities never fully left him. He talked of 'sleepless nights and days of acute fear' a maddening nervousness which prevented me from having a quiet moment.'
Yet others recognized in him extraordinary possibilities. Welch arranged a fellowship for him in Germany, and four years later he became professor of pathology at the Hopkins. Often he went into the field: to a mining town to study meningitis, to the Philippines to study dysentery, to Hong Kong to study plague. Nobel laureate Peyton Rous later called Flexner's scientific papers 'a museum in print, only they stir with life; for he experimented as well as described.'
He never lost his street toughness but his sharp hard edges did become rounded. He married a woman who was herself extraordinary enough to captivate Bertrand Russell (sixty letters from him were in her papers) and whose sister was a founder of Bryn Mawr. The famed jurist Learned Hand became a close friend. And he left his mark on the Rockefeller Institute.
Emerson said that an institution is the lengthened shadow of one man, and the institute did reflect Simon Flexner. Raymond Fosdick, later president of the Rockefeller Foundation, talked of the 'steely precision of his reason. His mind was like a searchlight that could be turned at will on any question that came before him.' A Rockefeller researcher said he had 'a logic far beyond that of most men, final as a knife.'
But in place of the comfort and monastic purpose and intimacy that Welch gave the Hopkins, Flexner made Rockefeller sharp, edgy, cold. Once, when the usefulness ended of horses that had been immunized against a disease, then bled over and over to produce antiserum, he never considered turning them out to pasture; he considered only either selling them for slaughter 'to manufacturers or they can be bled further, with the idea of sacrificing them' (bleeding them to death for a final harvest of serum. He could dismiss a person as easily, ridding the institute of what he termed 'unoriginal' men as soon as he made that determination. The room most feared in the institute was Flexner's office. He could be brutal there, and several prominent scientists were afraid of him. Even at Flexner's memorial service, a Nobel laureate said, 'Individuals were as nothing to Dr. Flexner compared with the welfare of the institute.'
He sought attention for the institute from the press and credit from the scientific community. His own work created controversy. Shortly after the Rockefeller Institute was established, a meningitis epidemic struck the eastern United States. Desperate measures were used to fight the infection. Diphtheria antitoxin was tried, and some physicians even tried the ancient practice of bleeding patients. At the Hopkins, Cushing tried draining pus-filled fluid from the spinal canal.
At the Rockefeller Institute, the meningitis epidemic seemed a particular challenge. Rockefeller and Gates wanted results. Flexner wanted to produce them.
Ten years earlier William Park, who had perfected diphtheria antitoxin, had developed a serum against meningococci. In every laboratory test his serum had worked. But it had had no effect on people. Now two Germans developed a similar serum, but they injected it directly into the spinal column instead of into veins or muscle. Normally the mortality rate from the disease was 80 percent. In 102 patients they cut the mortality to 67 percent, suggestive but not a statistically significant improvement.
Still, Flexner's instincts told him it meant something. He repeated the German experiments. His patients died at a 75 percent rate. Instead of discarding the approach, however, he persisted; he began a long series of experiments, both in the laboratory, to improve the serum's potency, and physiologically, searching for the best way to administer it to monkeys. After three years of work, he settled upon the method: first, to insert a needle intrathecally (under a thin membrane lining the spinal cord (and withdraw 50 ccs of spinal fluid, and then to inject 30 ccs of serum. (Unless fluid was withdrawn first, the injection could increase pressure and cause paralysis.) It worked. In 712 people the mortality rate fell to 31.4 percent.
Physicians from Boston, San Francisco, Nashville (all confirmed the work, with one noting, 'Remarkable results were obtained in the use of this serum by the country practitioners.'
Not all accepted Flexner's role. Later, in a bacteriology textbook, Park implied that Flexner had contributed little to the development of the serum. Flexner responded with an angry visit to Park's lab; a shouting matching ensued. There would be further disputes between the two, public enough that newspapers reported on one.
Ultimately Flexner cut the death rate for patients infected by the meningococcus, the most common cause of bacterial meningitis, to 18 percent. According to a recent New England Journal of Medicine study, today with antibiotics patients at Massachusetts General Hospital, one of the best hospitals in the world, suffering from bacterial meningitis have a mortality rate of 25 percent.
He and the institute received massive amounts of publicity. He liked it and wanted more. So did Gates and Rockefeller. In the first decade of the institute especially, whenever someone there seemed on the edge of something exciting, Flexner hovered about. His constant attention seemed to demand results, and he routinely urged investigators to publish, writing, for example, 'In view of the rapidity with which publications are appearing from Belgium and France, I advise the publication of your present results. Please see me about this promptly.'
The pressure did not all come from Flexner. It simply flowed down through him. At a 1914 dinner Gates declared, 'Who has not felt the throbbing desire to be useful to the whole wide world? The discoveries of this institute have already reached the depths of Africa with their healing ministrations' . You announce a discovery here. Before night your discovery will be flashed around the world. In 30 days it will be in every medical college on earth.'
The result was a publicity machine. Highly respected investigators mocked the institute for, said one who himself spent time there, 'frequent ballyhoo of unimportant stuff as the work of genius' because of 'administrators and directors impelled by the desire for institutional advertising.'
Yet Flexner also had a large vision. In his own work, he had what Welch lacked: the ability to ask a large question and frame it in ways that made answering it achievable. And when he judged an investigator original, an asset to the institute, he gave his full support. He did so
with Nobel laureates Alexis Carrel and Karl Landsteiner, both of whose work was recognized early, but he also gave freedom and support to young investigators who had not yet made their mark. Peyton Rous, whose undergraduate and medical degrees both came from the Hopkins, would win the Nobel Prize for his discovery that a virus could cause cancer. He made that finding in 1911. The prize did not come until 1966. Initially the scientific community mocked him; it took that long for his work first to be confirmed, then appreciated. Yet Flexner always stood by him. Thomas Rivers, a Hopkins-trained scientist at Rockefeller who defined the difference between viruses and bacteria, recalled, 'I am not saying Flexner wasn't tough or couldn't be mean (he could, believe me (but he also was tender with people.'
Even in a formal report to the board of scientific directors, thinking of Rous perhaps, or perhaps Paul Lewis, an extraordinarily promising young scientist working directly with Flexner, Flexner said, 'The ablest men are often the most diffident and self-deprecatory. They require in many cases to be reassured and made to believe in themselves.' When another scientist Flexner had faith in wanted to switch fields, Flexner told him, 'It will take two years for you to find your way. I won't expect anything from you until after that.'
And finally Flexner believed in openness. He welcomed disagreement, expected friction and interaction, wanted the institute to become a living thing. The lunchroom was as important to Flexner as the laboratory. There colleagues working in different areas exchanged ideas. 'Rous was a brilliant conversationalist, Jacques Loeb, Carrel,' recalled Michael Heidelberger, then a junior investigator. Although Rous and Carrel won the Nobel Prize, Loeb may have been the most provocative. 'These were really remarkable sessions sometimes. They were a great inspiration.'
Each Friday especially mattered; investigators routinely presented their most recent work in a casual setting, and colleagues made comments, suggested experiments, added different contexts. It was a place of excitement, of near holiness, even though some men (Karl Landsteiner, for instance, another Nobel laureate (almost never made presentations. Flexner actively sought out individualists who did not fit in elsewhere, whether they be loners or prima donnas. The mix was what mattered. Flexner, Rous said, made the institute 'an organism, not an establishment.'
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