Experiment Eleven (11 page)

As “consultant to the secretary of war,” Merck was personally receiving intelligence reports on enemy biological warfare. One such OSS report in August 1944 claimed that the German army had a “
special service
” in occupied France that was sending vials of cattle plague to England to be used for spreading epidemics among British livestock. The German agents in Britain were supposedly to infect the cattle when they were brought to market. In planning how to retaliate “in kind” if necessary, a “wide variety of agents pathogenic to men, animals and plants was considered.” This included many bacterial agents, such as bubonic plague and tularemia, against which streptomycin was the latest, and most effective, drug.

The War Production Board, now in control of U.S. industry, considered bringing streptomycin production under government control, as had been done with penicillin. But such a move would have required a special act of Congress. Unlike with penicillin, no government research funds had been allocated to the acquisition or distribution of streptomycin. Thus the government owned no rights to it. The drug had not even been cleared or approved by the Food and Drug Administration and therefore could not be sold publicly for therapeutic purposes, “
except to the federal services
”—i.e., the military, including the biological weapons program, or government agencies performing clinical trials.

In June 1944, Waksman formally asked Merck for the agreement of November 8, 1940, giving exclusive drug-development rights to Merck to be “abrogated.” As Feldman and Hinshaw at the Mayo Clinic announced the first successful guinea pig trials, George Merck ordered his legal staff to draw up a letter to Waksman ending their deal. The draft referred to unspecified “
correspondence and conversations
” with Waksman.

On August 17, 1944, this draft
became a formal letter
and was signed by Waksman and William Martin, dean of the College of Agriculture, and eventually by Rutgers president Robert Clothier. The final letter kept the same wording: “You have advised us of your feeling that you should be free to make available by [
sic
] other organizations antibiotic agents which may be of value to the armed forces in the present emergency.”

Later the agreement would be attributed by Rutgers to the fact that Merck and Waksman had realized that their cooperative enterprise had resulted in a great humanitarian discovery which should not be subject to an exclusive license. Accordingly, Merck & Co. Inc. had “
voluntarily abandoned
” its patent.

The return of the patent did not come free, as the fine print revealed. The company only agreed providing it could have a nonexclusive license and a new agreement “satisfactory to us.” In the new agreement, Merck demanded repayment of the estimated $750,000 worth of research it claimed to have carried out for Waksman on development work on streptothricin and streptomycin. This was mostly work done by the company's chemists in extracting and purifying the drugs. Rutgers eventually agreed to $500,000, which would be paid back to the company from Rutgers' future royalty earnings. Also, as part of the new deal, Merck agreed to continue to use its legal staff to make the patent application.

ON AUGUST 14,
1944, Waksman and Schatz filled out a standard
memorandum of invention
titled “Streptomycin and process for producing.” The date of the “conception” of the discovery was listed as August 23, 1943, the date of Experiment 11 on page 32 of Schatz's notebook. The first verbal disclosure was on September 10, 1943, when Schatz told Waksman's assistant, Robert Starkey. Waksman was apparently away. The first written description was recorded as October 8, 1943, and in Waksman's notebook as his Experiment 59.

The date of “reduction to practice” was put as November 22, 1943, corresponding to Experiment 72, on December 30, 1943, in Waksman's lab notebook. That experiment was titled “Influence of treatment on the extraction of streptomycin.” On the opposite page, Waksman wrote in later, “First time method of extraction of streptomycin
is described in detail
.” Thus, according to the patent application, Waksman and Schatz were officially “co-discoverers.”

The form was signed at Rutgers with Merck lawyers present. For the first time in their close relationship, Schatz questioned Waksman. He asked why they had to have a patent and why they had to use Merck lawyers. The university was an independent institution; why did they have to be involved with a commercial concern? For the first time, Schatz stood his ground with Waksman. “Streptomycin was the fruit of my labors. I felt that anything pertaining to human health and human life should be made available as quickly and as cheaply as possible to all people ... I didn't want to have anything to do with Merck,
whose interests were profits
,” he recalled telling Waksman.

Waksman replied that they had to go ahead with the patent to protect streptomycin. Without a patent, a company like Merck, Squibb, or Pfizer might produce a derivative of the drug, take out a patent, and control production and prices. Merck had patent lawyers who were able to help Waksman and Schatz with the application, a service that would otherwise have been expensive and was something Rutgers could not afford. Schatz would later remark, “Until then, the thought of patenting had never entered my head.”

BEFORE THE YEAR
was out, the first publicly recorded tests on human patients were carried out in New York and at the Mayo Clinic. Both tests were successful.

On September 21, 1944, a two-week-old infant arrived at Columbia University Babies Hospital, in New York, suffering from a bacterial infection that had caused meningitis, septicemia, and a “heavy urinary tract infection.” The infant was deeply jaundiced, and his liver and gallbladder were enlarged. The doctors gave him a sulfa drug, sulfadiazine, combined with penicillin, but the infant's fever remained high, and he was clearly dying.

In desperation, but with no clinical data to support their decision, the doctors switched to streptomycin, administering it every three hours for five days, then doubling the dose on the last, the sixth, day. The infant's temperature suddenly dropped, and he recovered. A memo of the event stamped “Secret: not to be disclosed
without special permission
” appears in Dr. Waksman's archives. One of the doctors wrote, “The medical staff at Babies Hospital are naturally very much interested and excited about this case. They have no doubt that streptomycin produced the favorable change in the clinical procedure.” There is no record of whether Waksman was involved or who had provided the streptomycin. It could have come directly from Merck and Waksman may not have been involved. Merck was testing streptomycin on mice, rats, guinea pigs—and humans. Merck had also tested streptomycin on six patients suffering from Gram-negative bacterial infections. The
results were mixed
. An adult woman with endocarditis—infection of the heart lining—and an infant with sepsis died after treatment. The antibiotic had no effect on a child with tuberculosis and meningitis, or on another with brucellosis. An adult with typhoid fever recovered. The drug had promising results on a patient with pneumonia.

On November 20, 1944, Patricia, a twenty-two-year-old farmer's daughter, lay dying in a hospital bed at the Mineral Springs Sanatorium, in Cannon Falls, Minnesota. She was suffering from advanced and spreading pulmonary tuberculosis, the most common kind. Patricia had been in the sanatorium for more than a year under the care of Dr. Karl Pfuetze, the medical superintendent of the sanatorium, and his assistant Dr. Marjorie Pyle. They had treated Patricia with the conventional forced bed rest. After initial improvement, she had deteriorated. Her right lung was badly diseased, and she suffered from alternating chills and high fever, sweating, and a worsening cough. The doctors considered her to be near death, and recommended that she be transferred to the Mayo Clinic for an assessment by Dr. Hinshaw.

With Patricia's consent, Hinshaw immediately started a course of streptomycin injections, using his limited and impure supply. He could only guess at the proper dose, and he was cautious at first, steadily increasing the dose until Patricia showed signs of improvement. The infection, which had spread to her left lung, gradually disappeared. Eventually, the doctors were able to operate on the right lung, removing the diseased section. Patricia made a remarkable recovery and was released from the sanatorium. She eventually married and had three children.

Within a week, in collaboration with Pfuetze, Hinshaw started to give streptomycin to twenty-two patients from the Mineral Springs Sanatorium; eighteen improved. These were Hinshaw's “scouting phases,” and he played down the results. He emphasized that many forms of TB “tend to improve spontaneously without treatment,” and that no single drug was likely to have “a rapidly curative effect” in a disease with the clinical pathology of TB. He did “not expect improvement” in less than a few weeks, nor did he expect clinical arrest of the infection in less than a few months. He pleaded for “extreme conservatism” in judging clinical results regarding chemotherapy and TB.

Feldman and Hinshaw refused to talk to newspapers about the results unless they were allowed to check and edit the story. Reporters also had to clear their copy with the Minnesota State Medical Association's Committee on Tuberculosis. The newspapers cooperated. Feldman and Hinshaw were equally cautious in articles published in medical journals,
avoiding overly optimistic statements
that might mislead the medical profession. They pointed out that extensive and prolonged clinical investigation would be required to determine the place of streptomycin in the treatment of TB.

On January 20, 1945, however, the successful end of the third and largest guinea pig trial was a real cause for celebration. Feldman cabled Waksman, “
Long term crucial
experiment streptomycin terminated today. Incomplete results indicate impressive therapeutic effects.” In a follow-up letter, Hinshaw wrote, “The results are sufficiently encouraging to be tantalizing ... If we could give a million or more units a day we might have something more impressive.”

Also at the end of January the Mayo researchers completed the first clinical trials on patients from the Mineral Springs Sanatorium. They reported a total of
fifty-four cases of TB
in which the patients had received streptomycin for a period in excess of four weeks, and the number of cases had increased to seventy-five by June. For the first time, they found some toxicity affecting the eighth cranial nerve, resulting in some dizziness. It was a small note of caution in an otherwise optimistic report.

The U.S. government prepared to set up a distribution network similar to the one used for penicillin, so that limited supplies would go to the army first. Merck sent small quantities to the Army Medical Corps, the U.S. biological warfare program at Fort Detrick, and the British chemical and biological warfare establishment at Porton Down, in Wiltshire, where they were testing streptomycin against an array of toxins. The official view was still cautious. Norman Kirk, the U.S. surgeon general, warned that “
no conclusive statements
” could yet be made as to the drug's potential because it was in such short supply.

A team of fifty Merck scientists was assigned at once to do everything possible to transform streptomycin from an extremely promising experiment into a therapeutic agent ready for use by doctors around the world. Merck broke ground on a $3.5 million plant, slated to employ four hundred workers, in Elkton, Virginia. On February 8, 1945, Merck lawyers filed the patent application papers of Selman Waksman and Albert Schatz for “Streptomycin and Process of Preparation.” The application included an oath, sworn by Waksman and Schatz, that “they verily believed themselves to be the original, first and joint inventors” of streptomycin, plus an affidavit of Waksman's describing streptomycin as “the new antibiotic that
Schatz and I have discovered
.”

AT THE BEGINNING OF 1945, AS
the Allied armies in Europe prepared for the final push to Berlin, Albert Schatz was about to turn twenty-five. He planned to mark his surprising yet spectacular contribution to the war effort with a rare personal celebration. He was going to marry Vivian Rosenfeld, a bright, pretty, blue-eyed student with long dark curly hair who was studying biology at the New Jersey College for Women, on the Rutgers campus.