• • •
It quickly became apparent that the vaccine produced in puppy cells by Philips Roxane was unacceptable. Not only did it cause arthritis and joint pain in women, but children, who rarely got arthritis after vaccination, began getting it after they received the vaccine, which went by the trade name Rubelogen. The children suffered arthritis in their knees, wrists, and hands. Some had carpal tunnel syndrome. The inflammation could last for weeks, and in nearly 30 percent of children, and probably more, it recurred.51 Other kids came down with a strange, painful nerve syndrome that woke them at night with hand, arm, and wrist pain and in the morning with pain behind their knees that caused them to hobble around in what was nicknamed the baseball “catcher’s crouch.” This syndrome too could persist for months.52
Within months state agencies began returning the dog-kidney vaccine, unused, to the company and refusing to accept new shipments.53 In September 1970, nine months after it was licensed, federal government agencies began refusing to buy it.54 The company withdrew the vaccine from the market in 1972.
And what of Smith, Kline & French’s enthusiastic backing of Plotkin’s vaccine? Two events early in 1970 torpedoed the collaboration. One was the DBS’s licensing of the company’s Cendehill vaccine. The other was the resignation, just weeks before the Cendehill vaccine was licensed, of Plotkin’s patron at the company, Ferlauto, who suddenly retired to Puerto Rico.
“There [is] probably no one at SK&F now that would really push the program,” Koprowski’s deputy, Norton, wrote in a memo to his boss and to Plotkin, after taking a phone call from the company with the news of Ferlauto’s departure.55 He was right. Several months later the company dropped development of Plotkin’s vaccine. Norton called Plotkin, who was at a meeting in Zagreb, to break the news.
In the United States Plotkin’s vaccine had hit what seemed to be a final, insurmountable wall. The huge U.S. vaccine market had become the property of Merck and of Smith, Kline & French and their respective duck embryo and rabbit kidney cell–propagated vaccines.56
• • •
Events in Europe couldn’t have been more different. Shortly after he returned from Zagreb, Plotkin wrote to Hayflick at Stanford, letting him know that the meeting participants had done some back-of-the-envelope math and concluded that about four million people worldwide had been vaccinated with WI-38–based vaccines. He added: “You will be glad to know that [WI-38] rubella vaccine is now licensed in France and Yugoslavia [and] is on application in the UK.”57 The UK would license the vaccine on December 29, 1970, and Burroughs Wellcome would quickly bring it to market. Separately, Pfizer was preparing to apply for licenses in the UK and the United States to market polio vaccine made in Hayflick’s human diploid cells. On the other side of the world, the Australian government’s vaccine maker, the Commonwealth Serum Laboratories, was busy outfitting the facility where Plotkin’s rubella vaccine would be made; Hayflick would travel to Melbourne in March 1971 to advise the Australian scientists. In the country where the ophthalmologist Norman Gregg had first recognized congenital rubella, it was the WI-38–propagated vaccine that the government would deploy to eliminate it.
CHAPTER SEVENTEEN
Cell Wars
Stanford, California, June 1968–December 1969
The entire history of our development of the human diploid cell strains is a litany of failures, disappointments, misunderstandings, and, finally, law suits. Yet, it is not without humor.
Leonard Hayflick, 19841
When Hayflick arrived at Stanford in the summer of 1968, he had neither house nor lab. The family rented a temporary home near the campus fraternity houses. There they waited for fifteen months while a new, boxy house of yellow ocher was built just for them on a quiet enclave called Mears Court, in the comfortable neighborhood that students ironically call the Faculty Ghetto. It had five bedrooms, and even a small study for Hayflick. There were almond trees in the yard and a magnolia with huge white blossoms that was spectacular in the spring.
As for the precious trove of original WI-38 cells, Hayflick recalls leaving them, while he waited for his lab to get up and running, with a highly qualified friend and colleague, Walter Nelson-Rees, who helped run the cell-culture facility at the Naval Biological Laboratory across the San Francisco Bay in Oakland. (Hayflick also remembers that a Nelson-Rees lab technician thawed and expanded several of the WI-38 ampules without permission, just out of curiosity, setting Hayflick’s teeth on edge when he learned of the loss.)
After the cold, gray winters and humid summers of Philadelphia, Stanford made for a welcome change. Eleven-year-old Joel admired the limpid light. Ruth, who had been looking forward to living in California, found that the bucolic campus, with its red tile roofs and sandstone masonry, its fragrant eucalyptus and its legions of tanned, bike-riding undergraduates, didn’t disappoint. The faculty wives were friendly. She learned that, as a spouse, she could attend classes. She enrolled in a biology course and met a friend who, like her, was an artist. Soon she was grabbing what time she could as a mother of five young children to attend the Palo Alto Art Club and to use the printmaking press in her new friend’s garage.
For an ambitious biologist like Hayflick, Stanford could hardly fail to be a draw. Joshua Lederberg had founded the Department of Genetics a decade earlier, just after winning a Nobel Prize for discovering how bacteria transfer genes. Arthur Kornberg in the Department of Biochemistry had won a Nobel in 1959 for elucidating how DNA is built. His biochemistry colleague Paul Berg, who would soon take over from Kornberg as chair of the department, would win a Nobel in 1980 for being the first to splice genes from different organisms together. The trio of “Bergs” made Stanford a mecca at a time when the frontiers of biology were expanding in thrilling ways.
Admittedly, Stanford’s Department of Medical Microbiology, where Hayflick became a professor, was not on a par with the Bergs’ dominions. Even before accepting the job, Hayflick knew that the department was a backwater, a fact reflected by its quarters in a remnant of the old museum that had been two thirds destroyed in the huge 1906 earthquake. But that left plenty of room for him to blaze a path of his own.
The department didn’t have room for Hayflick’s lab in the turn-of-the-century building that it shared with the anatomy department. Instead Hayflick was given a Butler building: a rectangular, prefabricated structure of about a thousand square feet. It stood on a patch of gravel that also served as a parking lot, between the medical microbiology building and the back of the university museum. Across the gravel patch, up against the anatomy building, was a kennel of narcoleptic dogs kept by the pioneering sleep researcher William Dement. His staff regularly let the small black and white dogs out to run in the parking lot, where they would sometimes fall asleep in midstride. (Hayflick also parked the family car here during Saturday football games, to avoid paying for parking near the Stanford Stadium across the campus, his son Joel recalls.)
The Butler building was an empty shell, and the Hayflick lab had to be built from scratch, which took months. In the meantime hollow doors served as lab benches and Hayflick created the “walls” of an office for himself by stacking cardboard packing boxes. Within a couple of years Hayflick found NIH funds to help him expand the lab: a double-wide trailer was positioned at one end, and a door was built connecting the two buildings.
After the addition the lab—dubbed “the Cancer Virus Building” for the NIH program that funded it—had a corner room for two secretaries, an office for him next to that, a warm room for incubating cells, a large liquid-nitrogen freezer, and enough common lab space to accommodate technicians, graduate students, and visiting colleagues.
The Hayflick lab was a hive of activity occupied by, among others, an excitable junior technician from Iran whose true desire was to be a banker and who drove his green Volkswagen Beetle around the campus like a maniac; and Eric Stanbridge, a blue-eyed, thin-lipped PhD student who had already worked under Ha
yflick at the Wistar. Woodring “Woody” Wright, a brainy Harvard graduate with a red beard and earnest brown eyes, would arrive in 1970 to complete his PhD in Hayflick’s lab, at the same time as he charged through an MD at the medical school. The mainstay of Hayflick’s support staff was his highly capable technician, Nancy Pleibel, a tall, athletic twenty-eight-year-old who had studied chemistry at Penn State and resisted her parents’ urgings to become a gym teacher. She had wanted to be a lab technician since she was twelve years old, and after she joined Hayflick’s Wistar staff in 1963 or 1964, she advanced to become his chief technician and followed him from Philadelphia to Stanford.
The lab was nothing special, and its subpar air-conditioning meant that it could get uncomfortably hot during the summers. But it was Hayflick’s, right down to the custom-labeled glassware, which announced, in big, brown, permanent uppercase letters, one word: HAYFLICK.
• • •
During the hot, humid East Coast summer of 1968, the Wistar Institute’s scientific administrator, a PhD microbiologist named Robert Roosa, was in Toronto, Canada, attending a tissue-culture meeting with his Wistar colleague Vince Cristofalo, a rotund, phlegmatic native Philadelphian with six daughters who had nonetheless found time to become absorbed by studying aging in Hayflick’s fetal cells. Roosa was sought out and summoned to the telephone. On the line was Hilary Koprowski’s secretary. She told him and Cristofalo to drop everything and fly back to Philadelphia immediately. The Wistar’s chief needed to speak with them on a matter more urgent than anything taking place in Toronto.
At the Wistar Roosa found Koprowski “rushing around” his office, beside himself. The precious, young, original WI-38 cells were gone. Hayflick had made off with every last ampule. Koprowski was furious. Pacing back and forth, he asked Roosa and Cristofalo whom they thought the WI-38 cells belonged to. “He was excited,” Roosa recalled. “We were just speculating on how much those cells were worth. To Hilary, they were worth a lot.”2
Before long, Koprowski sent Cristofalo to Stanford to try to secure, at a minimum, the ten ampules of cells that belonged to the Wistar under the January agreement. Hayflick recalls someone—he doesn’t remember who—from the Wistar arriving in his Stanford lab to demand the cells. He remembers feeling annoyed and sending the person back to Philadelphia empty-handed, claiming that he needed lead time and he wouldn’t just hand over the cells when the request was sprung on him.3
Cristofalo, who died in 2006, recalled the following episode in an interview with Roger Vaughan, who published a biography of Koprowski in 2000. Vaughan writes:
Koprowski sent Cristofalo out to get Wistar’s share back. He flew to California only to be stonewalled by Hayflick. “We had words,” Cristofalo says. Koprowski had a session on the phone with Hayflick, and told Cristofalo the deal was all set. Again Cristofalo flew to California. “Hayflick asked me if I had a container. I told him yes, liquid nitrogen. He asked me if it had been tested. He said unless it tested good for seventy-two hours, he wouldn’t let me have the cells. I told him it was brand new, and that we were talking about a ten-hour trip, maximum. Again he refused. Again we had words.”4
Hayflick’s departure with the cells became known to those who relied on them very soon after he left Philadelphia. Koprowski was “enraged,” recalls Plotkin, who wrote to Hayflick after he had been on the job at Stanford for precisely nine days.5 “This is to remind you of our discussion concerning WI-38. As soon as you have reconstituted the ampule, we would appreciate receiving a culture. Similarly, we would like to receive a culture from each subsequent ampule. I hope things are going well in California.”6
Other WI-38 cells were not by any means unavailable at this point. Scores of scientists across the country and around the world had them growing in incubators or tucked away in freezers. The ATCC, the well-known cell repository in Rockville, Maryland, already had in its possession about one hundred ampules of cells that had doubled fifteen times, which were useful for research.7 But it was the original eighth- and ninth-passage ampules of WI-38 that were golden to vaccine makers, because the cells were so young and so immensely, exponentially expandable. It was hundreds of ampules of these original, oh-so-young cells that Hayflick now watched over at Stanford like a jealous mother hen.
• • •
Hayflick was soon just as busy at Stanford as he had been at the Wistar. He continued his research on Mycoplasma, the tiny organisms that he had studied as a PhD student. The microbes were the subject of about half of the scientific papers and articles that he published during the late 1960s. Most of his other publications continued his campaign to get WI-38 accepted for making viral vaccines.
When Hayflick had left the Wistar in mid-1968, it had seemed to the experts at NIH’s cancer institute that the scientific need for the WI-38 cells had been sated.8 So the agency had let lapse his contract to provide the cells to scientists. But one year later Donald Murphy, an enterprising project officer in a different part of the NIH, realized that the demand for the cells hadn’t waned among scientists in the active and growing field of cellular aging. The WI-38 cells were perfect vehicles for examining the aging process—a field that Hayflick and Moorhead had thrown open with their landmark 1961 paper noting that normal cells aged in the lab.
So in mid-1969 the NIH awarded a new contract to Stanford, with Hayflick as principal investigator and Murphy as the project officer. Hayflick was hired again to produce, study, store, and distribute the cells on the NIH’s behalf, this time to biologists doing research on aging.9 (Murphy did not know that Hayflick had taken the cells to Stanford against the wishes of the NIH’s cancer institute. It was a case of one arm of the NIH not knowing what the other was doing.)
But in the meantime, during his first year at Stanford, from July 1968 through June 1969, Hayflick kept distributing the WI-38 cells as he saw fit. He sent twenty-seven original eighth-passage ampules to the Medical Research Council in London, three to the USSR, and five or ten to Drago Ikić, the vaccine master at the Institute of Immunology in Zagreb.10 He also thawed eleven of the eighth-passage ampules and expanded their cell populations until they had doubled between nine and twelve times, then sent the resulting cells, in bottles, bathed in medium, to scientists. Keeping up with the brisk demand for these dozens of “starter cultures” had him thawing an original eighth-passage ampule every four to six weeks, as he had already been doing for several years.11
Hayflick simply ignored the January 1968 agreement and the February 1968 follow-up letter from the NIH to Koprowski, stating that the agency owned the cells and that it was now “official policy” that no more eighth-passage ampules should be thawed and expanded.
Since he didn’t have NIH contract support in this first year that he was at Stanford, Hayflick began charging $15 to offset the costs of growing, preparing, and shipping the cells—less, he noted to a meeting of cell-culture experts, than the $25 that the nonprofit ATCC was charging for older, fifteenth-passage WI-38 starter cultures.12 “These funds,” he told his colleagues, “are used to defer [sic] charges for postage, glass-ware, packaging and culturing these cells for distribution.”
In November 1968 he established a fund at the university called “Medical Microbiology—Culturing Expense,” and deposited the money there.13 He would eventually, he told himself, get the lawyers to sort out who owned the cells. In the meantime the funds could simply accumulate.
Once the new NIH contract to distribute the WI-38 cells for aging research became operative, in June 1969, Hayflick began shipping the cells for free to researchers studying aging. The contract covered those costs. But he continued to charge costs when others asked for the cells. He made no exceptions for researchers at the NIH, where his paying customers included the Division of Research Services and scientists at the agency’s environmental health institute.14 (Both groups of NIH purchasers would later explain that they thought Hayflick owned the cells and had no idea that the NIH claimed title to th
em.)15 Hayflick also charged his former Wistar Institute colleagues, writing to Plotkin at one point in 1969 to ask why he had not received the $15 payment for two cultures he had shipped over the past several months. Was it simple negligence, or had the institute adopted a policy of not paying him? Plotkin soon wrote back to say that he had nudged the appropriate party to make the payment.16
• • •
After Wistar scientist Vince Cristofalo failed to retrieve the WI-38 cells from Hayflick at Stanford, another Koprowski emissary finally succeeded. On January 3, 1969, Pavel Koldovsky, a Czech physician who was then a visiting scientist at the Wistar, collected ten original eighth-passage ampules from Hayflick and returned them to the Philadelphia institute.17
Nonetheless, it seems that Koprowski kept up the pressure on Hayflick to return more of the hundreds of remaining original WI-38 ampules, and that Hayflick responded by trying to wrest from the Wistar’s boss a written assurance that, if he did, Koprowski wouldn’t turn around and sell the cells: Plotkin wrote to Hayflick in March 1969 telling Hayflick, “Naturally everyone disclaims the intention to sell WI-38,” but that if he wanted something in writing, he would have to get it from the board of managers.18
The Vaccine Race Page 32