The Vaccine Race

by Meredith Wadman

  At home there was the matter of keeping his family afloat. He began collecting unemployment compensation, which brought in $104 every other week. The Hayflick family, with two children in college, a high school senior, and ten- and thirteen-year-old girls, began living on savings, and on the fraction of his former income that Hayflick brought in from consulting jobs.

  Hayflick found some relative peace during his frequent trips to Maryland to consult for Microbiological Associates, the laboratory supplier. The facility in rural Walkersville was surrounded by cornfields and farms. The quiet was a tonic, “because there was a point before that time that whenever the phone rang it sounded like a bomb going off because so many phone calls held bad news.”27

  At one point, appearing anguished and aggrieved, Hayflick sent a letter of nearly two and a half single-spaced pages to Plotkin, attaching his eleven-page court complaint and a copy of his press statement.

  Plotkin’s reply was one paragraph long.

  Dear Len,

  I was very glad to hear from you and I wish you well in your legal endeavors. However, my major wish for you is that you have the opportunity to start doing science again at which you are so good. The main advantage of having a profession is to some extent one can submerge one’s other problems in one’s work, something which I have learned from my own experience.

  With warm regards,

  Sincerely yours,

  Stanley A. Plotkin, M.D.28

  • • •

  It was late summer, five months after the Schriver report was released, when the NIH made Hayflick’s sixty-five-page rebuttal publicly available to anyone willing to pay $11 for copying costs.29 (On September 1 Schriver completed his point-by-point rebuttal of Hayflick’s rebuttal. It was nearly twice as long because it reprinted Hayflick’s arguments and responded to each of them.)30

  There was little if any news coverage of Hayflick’s long retort, beyond a mention by Wade in a Science article, noting that Hayflick’s rebuttal was now available and that it called Schriver’s report “incomplete, inaccurate, and accusatory without proper cause.”31

  Hayflick made many points in his rebuttal. He contended that it was he, Hayflick, who first asked the NIH to investigate the legal status of the cells. He also insisted that his decision, after the Schriver investigation was launched, to remove his name from consideration for the directorship of the National Institute on Aging was made because of many concerns, including the impact that the new job would have on his time for research and the salary cut he would have to take. (Schriver had reported that a conflict clearly existed between Hayflick’s activities as president of Cell Associates and the duties of the NIA director. “During our initial discussion with Dr. Hayflick he apparently recognized this and decided to withdraw his name from consideration,” Schriver wrote.32)

  Hayflick also, in a stretch, assailed the Schriver report’s silence on the fact that Hayflick had filed suit against the government claiming ownership of the WI-38 cells.33 The Schriver report was completed in January, but Hayflick argued that the NIH could have amended the report after he sued the agency on March 25. This was the very day that, after a court declined to intervene to block its release, the NIH released the Schriver report to reporters under the Freedom of Information Act.

  Hayflick complained that the report blithely declared the cells “the property of the United States government.” But “the lawsuit puts in issue [that] very question.” He did not broach the subject of how an argument could be made for his ownership of the cells.

  In his rebuttal Schriver came back at Hayflick on every issue that he raised. The NIH investigator wrote bluntly: “The lawsuit obviously could not have been mentioned in the report because litigation was started after the report was written.”

  Hayflick had argued that at the pivotal January 1968 meeting where participants including him decided on the disposition of the cells, no decision was reached as to who owned them. Schriver shot back that such a decision wasn’t needed—their ownership by the NIH was implicit in the decision made at that meeting: that all but a score of the ampules should go to the ATCC, to steward them on behalf of the NIH.

  Hayflick wrote that he “had never received a request from NIH or anyone else to return the cells to ATCC.” Schriver retorted that Boone, the rangy pathologist who was the NIH contract officer, had asked him to do just that in the autumn of 1968.

  Hayflick decried the report for imputing sinister motives to his less-than-perfect record keeping of the inventories of WI-38. Schriver shot back that the NIH had the right to expect minimum standards, and noted that when NIH scientists, accompanied by an FDA colleague, Hope Hopps, took an inventory of the WI-38 ampules in Hayflick’s lab before taking them away, they “expressed astonishment at the slovenly nature of the records and the slip-shod manner in which the ampules were stored.”

  As for his stewardship of the cells, Hayflick contended, he had filled requests for scientists and institutions “outside the contract” with cells he had already thawed for researchers studying aging, which “would have been otherwise wasted or destroyed.”

  Schriver retorted that those statements “are unsupportable and can only be regarded as self-serving declarations.” Hayflick’s own records showed, Schriver wrote, that Hayflick had shipped some 1,700 low-passage cultures while at Stanford and that, of these, nearly 1,200 had been shipped to paying customers. What was more, paying customers had received preferential treatment, frequently receiving younger cells than the researchers studying aging whom Hayflick supplied under the contract. “It is obvious that the interest of the government was not protected.”

  To explain how he could meet the terms of the Merck contract—to supply the firm with one hundred or more ninth-population-doubling-level ampules—by using just a handful of eighth-passage ampules, Hayflick again argued that he could do so by planting the cells in bigger-than-usual bottles, and giving them more room to expand, generating dozens of ampules’ worth of cells before they were harvested at the ninth passage. He also wrote that population-doubling estimations were so imprecise that it was meaningless to attribute significance to differences in population doubling levels of less than ten.

  Schriver, in his rebuttal, turned to Hopps of the FDA to respond. She wrote of Hayflick’s explanation of how he could generate enough cells to fulfill the Merck contract: “We cannot agree with Dr. Hayflick’s comments. Indeed, it is improbable that, on the basis of the number of [eighth-passage] ampules now known to exist, one could derive such a large number of ampules at the 9th PDL. It is possible that by manipulation he could have 9th passage cells, but not cells at the 9th population doubling.”

  Hayflick had the upper hand in the rebuttal only when he challenged the NIH’s passivity and tacit acquiescence in his activities.

  He noted that he had repeatedly reported, in his progress reports to the agency, that he was supplying the cells to off-contract scientists. In the face of this, he reminded readers, he had received repeated commendations for his management of the contract delivering cells to researchers studying aging. “At no time were Dr. Hayflick’s decisions or policies in this regard ever questioned by anyone,” he insisted. Failing to let the report’s readers know this, he argued, “unjustifiably distorted” the report.

  Hayflick also bemoaned the lack of context in the report:

  The report fails to state that Dr. Hayflick pioneered the freezing and preservation of human diploid cells and had them prepared at a time when the state of the art was very primitive. He learned that

  frozen ampules are very brittle and easily cracked;

  inexplicably, the bottoms of many ampules dropped out;

  a portion of ampules exploded upon withdrawal from liquid nitrogen; and

  ampules, once removed from holders, sometimes are dropped and irretrievably lost.

  What was more, he argued, freezers at the Wistar were reg
ularly unlocked and accessible to a variety of people over a six-year period.

  But Schriver responded with disbelief to Hayflick’s claim that only 139, not 207, ampules were unaccounted for and that all of these 139 had been lost, exploded, cracked, been contaminated, or died. Schriver called the claim “unacceptable.” He and his team had found, in the records both at the Wistar and Stanford, numerous instances where it was recorded when an ampule was cracked, exploded, contaminated, or dead. Given that, he wrote, “one is hard pressed to accept such a weak argument that the condition of the 139 unaccounted-for ampules would not have been recorded.”

  Several items in the dueling rebuttals come down to he-said-he-said arguments, like Hayflick denying that he ever told Schriver that he had behaved “improperly” and Schriver insisting that he had said just that. But on the facts of the sales to companies Hayflick’s rebuttal is either weak or silent. Of his transfer of two bottles of young cells to Connaught representatives in Montreal for an agreed-upon price of $5,000, he writes that this information “implies any number of negative conclusions about Dr. Hayflick without serving any legitimate purpose.” Therefore, he writes, investigators shouldn’t have included it. He does not dispute the $3,000 sale of cells to the Institute of Immunology in Zagreb. As for the Merck contract, Hayflick writes only that it was Merck who approached him, and not vice versa.

  “It is immaterial who first approached whom,” Schriver responded.

  Hayflick closed his rebuttal, which is stiffly couched in the third person, with what can only be termed a lament.

  The report concludes that Dr. Hayflick has acted in contravention of government property rights in the cells. That conclusion is wrong. . . . But what is so unfair about the report, and so terribly damaging to Dr. Hayflick, is not this wrong conclusion itself, but rather the report’s assertion that the issue of ownership has always been beyond dispute and that Dr. Hayflick appropriated government property intentionally and dishonestly with full recognition that he had no colorable right to do so. . . . It is a cruel irony that the report should fail to mention that there is a significant question as to ownership [of the cells]. . . . The injury to Dr. Hayflick’s reputation and career caused by the report is irreparable. He may never fully recover.

  Schriver’s conclusion was much briefer.

  Dr. Hayflick’s comments give NIH no reason to make any changes [in the report]. In fact, much of his material either cannot be corroborated or is in complete disagreement with the facts.

  Hayflick had willfully over the course of seven years created the circumstances that had brought his life crashing down around him. But once he had done so, the NIH was not going to show the slightest bit of give in how it dealt with him, especially not after he filed suit against the agency. There was an animus toward him in Bethesda—from Schriver and Jacobs and perhaps from other senior officials—that went beyond the facts of the case and was deeply personal; this would become apparent in the ensuing years.

  The dislike also extended to downtown Washington, DC, to the NIH’s parent, the Department of Health, Education and Welfare, where senior officials now set out to ensure that “doing science again,” as Plotkin had urged him to do, was not going to be easy for Hayflick.

  By January 1977 Hayflick had landed a position at a research lab at Children’s Hospital Medical Center, across the San Francisco Bay in Oakland. It was a place to hang his hat, but it was certainly no Stanford. What was more, he was not allowed to transfer to Oakland the multiyear NIH grants that he had won at Stanford, like a generous five-year grant to study how normal human cells became cancerous, which had been awarded only weeks before the Schriver report was published.34 The Oakland hospital was strapped and could in no way support his salary; Hayflick needed to bring in new grant money to fund his science, and he needed to do it quickly.

  Just ahead of a March 1, 1977, application deadline, he turned, with trademark tenacity, to the NIH’s National Institute on Aging, where an inaugural director, Robert Butler, was finally in place. Hayflick applied for a three-year, $562,000 grant to study aging in laboratory cells. As part of his application, he requested that the NIH provide him with the youngest WI-38 cells—in other words, some of those it had taken from his lab.

  In October the advisory council of scientists to the NIH’s new aging institute voted to fund Hayflick’s grant. Normally, such advisory councils vote to fund groups of grants, each of which has been closely scrutinized by a smaller group of scientific peer reviewers, as Hayflick’s had been.35 But in a highly unusual step, the aging institute’s advisers took a separate vote to approve the funding of Hayflick’s grant specifically.36 Their message to NIH administrators couldn’t have been clearer: Get off his back and let him do his science again. Then absolutely nothing happened. It would take another twelve months before the NIH informed Hayflick, after he obtained confidential correspondence between the NIH and its parent department under the Freedom of Information Act and asked the NIH to explain it, that he would not see any money before the secretary of health, education and welfare conducted a special review.37

  Riseberg, the NIH legal adviser, had told the agency in 1977, after it received Hayflick’s new grant application, that there was “no sound legal basis” for categorically excluding Hayflick from winning NIH grants.38 Fredrickson, the NIH director, was of the same mind, and Butler, the inaugural director of the aging institute, agreed.39,40

  But Leon Jacobs, the NIH associate director, who had been quoted in Science saying that he doubted that the NIH would shut down Hayflick’s ability to win grants—and who was so aggrieved at Merck’s report that he had told the company that Hayflick owned the cells—disagreed, and let Frederickson know. The NIH “could administratively decide not to make the award [to Hayflick], on the basis of questions about Dr. Hayflick’s scientific integrity,” he wrote to Frederickson several months after Hayflick applied for the funding.41

  In downtown Washington more powerful players were in Jacobs’s corner. In early 1978 Thomas D. Morris, the inspector general for the Department of Health, Education and Welfare, wrote a memo to his Hayflick File, directing Riseberg and others to “develop a paper on . . . Secretary [Joseph] Califano’s discretion to withhold a grant award.” He wanted another paper on the importance of having NIH reviewers consider any grant applicant from a “managerial and ethical viewpoint.” In general, Riseberg and his colleagues were to “shape up the disqualification procedure.”42

  A few months later the inspector general dictated another memo to the Hayflick File. In it he directed an assistant to follow up with Riseberg regarding “the selection of an option by Dr. [Julius] Richmond [the assistant secretary for health] to preclude the award of grant involving Dr. Hayflick as its principal investigator.”43

  Hayflick would finally get his grant money—it’s not clear who at the department finally gave up on blocking it—in August 1979, two and one half years after he applied for the grant. It would deliver $562,000 over the coming three years. But Hayflick did little with it, and not only because the NIH refused to provide the young WI-38 cells that Hayflick insisted he needed for his studies.44 (The agency said that he could obtain older WI-38 cells at cell banks like the ATCC, just like other scientists.)45 Hayflick’s science had all but ground to a halt as he spent time fighting a lawsuit, trying to find a long-term job, and earning what he could from consulting, to keep his family fed. He would rarely publish new, lab-based experiments again.

  CHAPTER TWENTY-THREE

  The Vaccine Race

  Iran and the United States, 1975–81

  The sudden attack of a mad, foaming, and enraged animal . . . almost always takes place in daytime in the middle of the village and ends, after a frightful struggle, with the death of the wolf under the sticks and pick-axes of the peasants.

  —Marcel Baltazard and Mehdi Ghodssi, director and chief, respectively, of the Rabies Service at the Pasteur Institute of Iran, Tehran,
19541

  On October 20, 1975, as James Schriver was laboring over the report that would turn Hayflick’s world upside down, a rabid wolf attacked seven people in Aghbulagh, a rural farming village in northwestern Iran. The victims included a fifty-five-year-old man who sustained twenty lacerating face, head, and hand wounds, and a seven-year-old boy with more than twenty-five deep gouges to his head, neck, face, and ears. The mad wolf was at last cornered and killed by the terrified villagers. For the roughly sixty people in the village of mud-walled homes, the attack was a calamity.

  The roads were bad, and it was thirty-two hours before the victims, with the wolf carcass in tow, made it to the Pasteur Institute of Iran, a distance of a little more than 250 miles. The institute, which is independent of the famous French institution founded by the rabies vaccine inventor, Louis Pasteur, was a designated World Health Organization center for rabies research. The disease was endemic in both dogs and wolves in Iran, and the Tehran scientists, who still relied on vaccines made in animal brains, had recently been charged with conducting an important clinical trial.2

  The seven villagers were injected first with blood serum from mules, containing antirabies antibodies produced by Iran’s reputable Razi Institute. This was the transient, “passive” immunization that was, and remains, so important to holding the virus in check until victims can be vaccinated and their own immune systems begin to produce antibodies. Within an hour of this first jab, each of the seven villagers was also injected with the trial vaccine. Invented at the Wistar Institute in Philadelphia and produced by the Institut Mérieux in Lyon, France, it was made using WI-38—Hayflick’s human diploid cells. The trial vaccine had already been safety-tested in healthy volunteers, who had produced robust levels of antibodies. Would it work in humans bitten by rabid animals?