The Vaccine Race
Page 29
In September 1966 Perkins’s colleagues at the Medical Research Council, J. P. Jacobs, C. M. Jones, and J. P. Baille, received a fourteen-week-old male fetus following an abortion in a twenty-seven-year-old woman carried out, they later reported, “for psychiatric reasons.” From the lungs of that fetus they derived a cell line of typical, spindly fibroblasts. They named the line MRC-5, after the Medical Research Council, and published their work in Nature in 1970. The time lag allowed them to report that the woman had remained healthy and cancer free for three years following the abortion.
The Nature paper described the healthy, noncancerous characteristics of MRC-5 cells, along with their vigorous growth in lab bottles, their normal chromosomes, and their susceptibility to infection with a host of human viruses. The scientists wrote that they had frozen a big supply of the new British human diploid cells: 481 ampules. Their paper opened with an homage to WI-38 and closed with the same. “Our studies indicate that by presently accepted criteria, MRC-5 cells—in common with WI-38 cells of similar origin—have normal characteristics and so could be used for the same purposes as WI-38 cells.”4
Although neither Hayflick nor the British scientists could have imagined why it would become the case, that last fact—that MRC-5 cells could be used for all the same purposes as WI-38 cells—would become important.
• • •
As their prominence expanded, Hayflick was only too happy to promote the WI-38 cells. HUMAN CELLS GIVEN ROLE IN VACCINES, the New York Times proclaimed—hyperbolically—after Hayflick spoke at a vaccine conference in 1966. The article quoted Hayflick’s views—and only Hayflick’s views—as he explained that his cells were cheaper, cleaner, and safer than the animal cells used in vaccine making. “Today, a specialist in the growth of human cells in the laboratory said that research on the cells used in vaccine production had been seriously neglected,” the Times explained.5
A few months later, in 1967, after he spoke to an American Cancer Society seminar for science writers, Hayflick was in the Times again, promoting his cells as an alternative to disease-ridden monkey kidney cells.6
That same year Hayflick ran out of patience with Koprowski and his institute. The disconnect between his contributions and his treatment by the Wistar’s boss had become more than he was willing to tolerate. Nine years after Koprowski hired him, Hayflick remained stuck as an associate member of the institute, in sharp contrast to a coterie of his other Wistar colleagues who were full members and yet whose contributions were not, to his mind, any greater than his own. As an associate, not only did Hayflick make less money than full members, but his salary was not guaranteed by Koprowski should he fail to win NIH funding for his work.
Never mind that he was now a father of five who would have appreciated the job security. What galled him was Koprowski’s implicit refusal to credit his accomplishments: his discovery of the Mycoplasma that was the cause of walking pneumonia; his nearly simultaneous recognition that normal cells aged in lab dishes, and the huge scientific questions that it opened; his production of the WI-38 cells that could—that deserved to—supplant archaic methods of making antiviral vaccines; his tireless efforts to make that happen.
He was at bottom just a showy date for Koprowski, and a cheap one at that: early in 1967 he had just won a three-year renewal of the sought-after NIH Career Development award that had already fully funded his salary since 1962. What was more, his contract with the NIH’s National Cancer Institute—the big one to produce, store, and distribute his human diploid cells—had brought the Wistar more than $120,000 every year for five years now and was moving into a sixth year. That contract, among all of the contracts and awards that the institute’s scientists brought in, was consistently one of the largest.7
Fed up, Hayflick began looking around. He was offered the chairmanship of the department of microbiology at the University of Vermont in Burlington. He also applied for a position as a full professor of medical microbiology at Stanford University in Palo Alto, California. For the Stanford job he had help in high places: one of his recommenders was Albert Sabin, whose live oral polio vaccine, by then being used in most countries that vaccinated, had vaulted its inventor into the most prestigious ranks of U.S. medical science.
In August 1967 Sabin wrote to Sidney Raffel, a leading immunologist who was heading Stanford’s search for a new professor of medical microbiology: “In my judgment, he is a very reliable investigator who has exhibited considerable intelligence and originality in the work that he has done. I have a high regard for Dr. Hayflick because his contributions over the years have been sound and trustworthy.”8
Not long afterward, Hayflick was offered the Stanford job.
To Hayflick, the difference between the positions at Vermont and Stanford was akin to the difference between coaching for the Phillies and playing first base for the Yankees. His choice was easily made. In the autumn of 1967 Hayflick told Koprowski that he would be taking a professorship at Stanford beginning on July 1, 1968.
• • •
It seems likely, given his apparently low regard for Hayflick’s capabilities, that there was one thing, and only one thing, that concerned Koprowski about Hayflick’s impending departure: the fate of the hundreds of ampules of WI-38 cells that were still stored in liquid nitrogen in the Wistar Institute’s basement, under Hayflick’s watchful eye.
Koprowski had had designs on the WI-38 cells from the beginning. Nancy Pleibel, a lab technician who began working for Hayflick in 1963 or 1964, recalls that more than once as she learned the ropes, Koprowski turned up in the lab within a day or two of Hayflick leaving on a trip. Charmingly, smilingly, the Wistar czar would ask her for an ampule of WI-38 cells. Politely but firmly, she would refuse, explaining that only her boss could hand out WI-38 ampules. After a while Koprowski stopped asking her.9
Minutes from the Wistar’s board of managers meetings in the early and mid-1960s make clear that Koprowski tried repeatedly to cash in on the human diploid cells. The Wistar sought payment not only from Norden, a Missouri company that was interested in using WI-38 to develop the nascent rabies vaccine, but also from Pfizer for the use of Hayflick’s cells to make a measles vaccine, and from Wyeth, another Philadelphia-based drugmaker that by 1965 had used the WI-38 cells to make an adenovirus vaccine to protect U.S. Army recruits during basic training.10*
Koprowski’s attempts to turn a profit with the WI-38 cells were far from successful. By 1965 the board of managers had appointed “a special committee of lawyers and scientists to deal with problems” selling the Hayflick cells to industry.11 The only support that the institute landed, according to budget documents from 1965 to 1967, was $5,000 in each of those years from Norden.12
Today it seems incredible that an institution like the Wistar, full of sophisticated scientists, was so at sea when it came to profiting from unique and desirable cells produced under its roof. But in that era living things, like WI-38 cells, could not be patented. It would take a landmark Supreme Court decision in 1980 to change that. (Nonetheless, it appears that Koprowski or Hayflick did take steps to patent the cells, in 1966; a patent attorney they enlisted told them it was too late to even try as Hayflick’s discovery had been published in 1961 and the one-year window of opportunity for filing for a patent had closed.)13
However, what could be patented was a method of using the cells to produce a novel vaccine. Koprowski had already applied, back in 1964, for such a patent for the new, improved rabies vaccine that he and Wiktor were developing using the WI-38 cells. Soon the Wistar would apply for a patent on Plotkin’s method of making the RA 27/3 rubella vaccine.
If and when the rabies and rubella vaccine patents were granted, Koprowski’s access to at least some of the original ampules of WI-38 carefully frozen in the Wistar basement might be vital. Vaccine companies would want original ampules full of the youngest cells—cells that could be expanded exponentially into a nearly endless supply: original ampu
les that Hayflick had frozen in the summer of 1962, after their cells had divided just eight times; original ampules that were, Koprowski hoped, so much cellular gold.
By the autumn of 1967 Hayflick vaguely suspected, without having the corroborating evidence, that Koprowski intended the WI-38 cells to serve as something more than vaccine factories deployed for the good of mankind; that his boss hoped to turn any vaccines made with the cells into plentiful sources of cash, boosting the Wistar’s income and freeing Koprowski from the odious fund-raising duties that he considered beneath him and that had been the bane of his existence since he took the helm of the institute a decade earlier.
Hayflick’s instincts were right, and for understandable reasons: as the year 1967 drew to a close, a financial vise was tightening on Koprowski.
While the Wistar had remained solvent under its high-living boss, it had never been exactly flush with funds, especially after Koprowski blew through $271,506 to fund the major renovations that were completed in 1959. By the mid-1960s his struggle to find cash that wasn’t tied to specific grants was becoming acute. An operating loss of $12,000 in 1965 grew to some $23,000 in 1966, causing Koprowski to defer repairs. The windows in the seventy-three-year-old building needed replacing. So did the roof. The air-conditioning in some labs required new, high-end filters. The public toilets and the sewer system both needed overhauls.14
By late 1967, when Hayflick announced his impending departure, Koprowski was facing an expected 1968 deficit of $65,460—$469,000 in 2016 dollars—and board of managers members were calling for long-term solutions. Adding to the tightening financial screws was the fact that the NIH had recently launched a “high-priority audit” of the Wistar’s grants. The agency felt that Koprowski’s methods of claiming overhead costs—an important source of general-purpose funds for the institute—from individual scientists’ government grants were “in conflict” with agency regulations. The NIH aimed to apply the findings of the audit both retroactively and prospectively—meaning that Koprowski could soon owe the agency some unknown, and possibly frightening, amount of cash.15
• • •
In the autumn of 1967, when the NIH’s National Cancer Institute learned that Hayflick would be moving to Stanford in July 1968, officials there decided to end Hayflick’s contract to produce, store, and distribute human diploid cells to any qualified researchers who needed them. The cancer institute had been paying the Wistar hundreds of thousands of dollars for Hayflick to produce and distribute the cells ever since the contract was launched in February 1962, soon after Hayflick’s paper announcing his human diploid cell strains to the world sent demand for them soaring. Now, institute officials set January 1, 1968, as the end date. The timing seemed right, and not only because of Hayflick’s impending move. The sense at the government cancer research institute was that the demand for the WI-38 cells had been sated.16Those scientists who wanted them, it seemed, had them by now, more than five years after Hayflick had first produced them. They were being used widely and had already been cited in scores of papers.
On January 18, 1968, several men traveled from Bethesda to the Wistar Institute to sort out the physical disposition of the WI-38 cells now that the contract had ended. Koprowski summoned Hayflick to meet with them. One was Charles Boone, a tall, thin, edgy MD/PhD who since the previous May had been overseeing the human diploid cell contract for the NIH’s cancer institute. Also present were John E. Shannon and Marvin Macy, two senior scientists from the American Type Culture Collection. The independent, nonprofit ATCC, as it was popularly known, was housed in a boxy brick building in Rockville, Maryland, six miles from the NIH. It was the country’s highest-profile cell bank, and was often the repository that biologists turned to when they needed a certain type of cell for an experiment.
Hayflick joined the group in a small conference room. Also present was Koprowski’s deputy director for scientific administration, John D. Ross, who took notes and wrote up minutes of the meeting. According to these minutes, the assembled men agreed that all but twenty of the roughly 375 remaining original ampules of WI-38 cells would be transferred to the ATCC, which would maintain them, deeply frozen, on behalf of the NIH. Hayflick would be permitted to take ten ampules with him to Stanford, and the Wistar itself would be allowed to keep ten ampules.17
The group also decided that any use of the 355 precious original ampules being transferred to the ATCC—they were precious because the WI-38 cell populations in them had divided just eight times and so could be expanded into untold billions of cells for vaccine making—“should be totally arrested.” They meant that there was to be no more thawing of the ampules, no more planting of these young eighth-generation cells into lab bottles, and no more splitting of those bottles over and over to generate multitudes of cells at higher population doubling levels for scientists to use. Scientists could use the older cells that were already in wide circulation. The remaining 355 original ampules needed to be kept safely frozen at the ATCC until such time as companies began winning licenses from the DBS to make WI-38–based vaccines. Then, carefully, the ampules could be thawed one at a time, expanded through a handful more doublings, and handed out as needed to companies to make vaccines, the minutes specified.18
Before the meeting broke up, the group set a date for the transfer of the WI-38 cells from the Wistar Institute to the ATCC: March 1, 1968.
• • •
The dry, black-and-white minutes of that January 1968 meeting do not convey the subtext of what transpired that day, according to Hayflick, the only participant, except perhaps Boone, who is still alive. Nor, Hayflick says, does a letter sent from the NIH’s Boone to Koprowski four weeks later capture the subtext of that meeting. The letter formalized the decisions made on January 18 as “official policy” of the NIH. It concluded with a flourish that “the WI-38 cells . . . will remain the property of the NCI,” referring to the NIH’s National Cancer Institute.19
Hayflick said in a 2013 interview that he was compelled to attend the meeting and that he had no choice but to concur with the “alleged agreement” transferring the cells to the government, which was pointedly asserting its ownership. “It was not written by me; it’s written by five people who are saying, ‘You better agree to this.’ I have no muscle. What’s my muscle? Honor?”20 He also noted that he didn’t sign either the meeting minutes or the follow-up letter from Boone to Koprowski. He did get copies of both.
What Hayflick does not mention is the wording of the 1962 contract between the National Cancer Institute and the Wistar Institute that committed the institute, in the person of Hayflick, to produce, store, and distribute human diploid cells to qualified scientists. That contract, signed several months before he derived the WI-38 cells, addressed explicitly what was to happen when the contract was terminated: “The contractor agrees to transfer title and deliver to the Government, in the manner, at the time and to the extent, if any, directed by the Contracting Officer, all data, information and material which has been developed by the Contractor in connection with the work under this contract.”21
In the January 1968 meeting at the Wistar, the government’s contracting officer, Boone, had directed Hayflick on March 1 to deliver to the government, in the form of Boone and Shannon, all but twenty original ampules of the WI-38 cells.
• • •
Hayflick was unhappy after that meeting. He didn’t want to give up control of the WI-38 cells, and he especially did not want to cede them to the ATCC, whose past management of cells, in his experience, had been sloppy. So he stewed. But as January rolled into February, he did nothing else. It took a very specific event to precipitate an action on his part that would have profound consequences for his life and his career.
When he relates this event nearly fifty years after the fact, it’s clear that Hayflick can see it and feel it as if it had happened yesterday. His voice gets more intense. He is at pains to be clear.
Sometime during hi
s last months at the Wistar, he was working in one of the tiny “sterile” rooms that adjoined his lab. Plotkin squeezed in the door and pulled up the only other chair in the six-by-nine-foot room. The two chatted for a bit, and then Plotkin showed Hayflick the document that had brought him on this visit. It was a letter, on Wistar letterhead, from Koprowski, written to a senior official at Burroughs Wellcome, the British drugmaker. It was not a final document, or a contract, or a bill of sale. But it was definitely conveying the following: that Koprowski was offering to provide to the company ample supplies of WI-38 cells, along with the recipe for making a vaccine with the cells, and the vaccine virus itself, all in exchange for royalties.
Hayflick had suspected, but up until this moment had not known, that Koprowski planned to use the WI-38 cells to make as much money as he could for the Wistar—and to do so without so much as a by-your-leave from Hayflick. He was stunned and sat in silence. He did not think to ask Plotkin for a copy of the letter, or even to ask why he was showing it to him.
Plotkin does not remember this conversation at all, a fact that upsets Hayflick to this day. But in Plotkin’s papers there is a single sheet entitled “Chronicle Burroughs-Wellcome Proposed Agreement.” It lists, without detailing their contents, eight items of correspondence exchanged between the Wistar Institute and the company during 1968, beginning with a March 6, 1968, letter to Hilary Koprowski from a Dr. Edward at Burroughs Wellcome. Next there is a letter from Koprowski to Dr. Edward, dated March 14, 1968—after which lawyers and bankers take over the correspondence.22