Vaccinated (9 page)

Now that Plotkin had his virus, he had to find a way to weaken it. Whereas Hilleman and Meyer had used animal cells to weaken rubella virus, Plotkin wanted to use fetal cells. He didn't have to look very far to find them. Leonard Hayflick, who briefly shared a lab with Plotkin, was working with cells from a human abortion; he gave Plotkin the fetal cells that he needed to make his rubella vaccine. For his generosity, Hayflick would soon become the principal target of those opposed to using a human fetus to make a vaccine. Initially, Hayflick wasn't particularly interested in vaccines. He wanted to understand how and why we age.

 

T
HE WORLD
'
S OLDEST PERSON,
J
EANNE
C
ALMENT OF
F
RANCE, DIED IN
1997 at the age of 122, having far surpassed the average lifespan in most countries, which is 76. No matter how well we eat, how much we exercise, or how attentive we are to our own safety, we all will die. We die because our cells become less and less capable of doing what they are supposed to do: making needed enzymes, fighting infections, and resisting transformation to cancer. Hayflick wanted to understand why this happened. To do it, he started with the youngest cells he could find.

Leonard Hayflick was a native of west Philadelphia and a graduate of the University of Pennsylvania. His father made dental devices. To get the cells that he needed, Hayflick asked Sven Gard, a Swedish virologist and later member of the Nobel Prize committee, to provide him with a human fetus. “[Gard] had worked in the lab across from me,” recalled Hayflick, “and he said, ‘We can get you all of the fetal [organs] you want from Stockholm. You know we do this every day there, and it's legal. Let me talk to my colleagues and we'll set up a system.” Gard granted Hayflick his wish, sending him a female fetus aborted at the end of the third month of pregnancy. “The [fetus] came from a woman whose husband was a mariner,” recalled Hayflick. “He was apparently a drunkard and she didn't want more children. They didn't send the whole fetus. By that time, I knew what [organs] I wanted. I wanted a lung or a kidney. And so they removed these organs [and] put the material in cell-culture fluid, in test tubes or small flasks, packed it in wet ice, and sent it by air, just ordinary airmail.”

Hayflick found that fetal cells, placed in laboratory flasks, reproduced. If he took some of these cells and placed them in another flask, they reproduced again. But Hayflick also found that the number of times fetal cells reproduced wasn't infinite. After about fifty doublings, cells would deteriorate and die. “I didn't think very much of it initially,” recalled Hayflick. “I just thought everybody knew…that normal cells could not divide infinitely; only cancer cells were immortal.” Hayflick demonstrated in the laboratory what had been posited by the German biologist August Weissman eighty years earlier: “Death takes place because cell division is not everlasting but finite.”

The phenomenon of limited cell doublings is called the Hayflick limit. At first, researchers thought that Hayflick was merely observing a phenomenon unique to cells growing in laboratory flasks and that cells could reproduce forever under the right conditions. But Hayflick found that cells always knew exactly how many times they had reproduced. If he took cells and froze them for months or years, thawed them out, and placed them back in laboratory flasks, they would pick up right where they had left off, doubling a total of fifty times. Hayflick's work seemed to contradict that of Alexis Carrel, the man who kept the chicken heart alive in his laboratory for thirty-two years. But Carrel had unknowingly cheated. While nourishing the heart with crude extracts made from chicken embryos, technicians were inadvertently adding new cells to the culture. “Alexis Carrel was an egomaniac,” recalled Len Hayflick. “The technicians knew that chicken cells were contained in the chicken-embryo extracts they were adding to the heart. But they were scared to tell Carrel, worried that it might torpedo his career and that they'd get fired.”

In one brilliant experiment, Hayflick proved that it wasn't the conditions of growth that determined how long cells could reproduce. He took female fetal cells that had reproduced ten times and male fetal cells that had reproduced thirty times. Then he put the two groups of cells in the same flask to see how many more times each would divide. Because only male cells had a Y chromosome, he could tell which cells were male and which were female. Hayflick found that under the exact same growth conditions, the female cells divided forty more times, but the male cells only twenty more times. It was as if each cell had an internal clock that dictated how long it was supposed to live.

Later, Hayflick and other researchers figured out why cellular replication isn't infinite. Essential to cell life and growth are the cell's genes, which are encoded on long strands of a chemical called deoxyribonucleic acid (DNA). When cells duplicate, DNA is also duplicated. Responsible for duplicating DNA is an enzyme called DNA polymerase. To begin the process of DNA replication, the polymerase sits on top of DNA as a train sits on top of a track. The train (polymerase) moves forward and reproduces the track (DNA) in front of it but not the small part of the track initially under it. That means the polymerase doesn't reproduce all the DNA. So each time a cell reproduces, its DNA gets a little shorter and shorter. James Watson, who with Francis Crick was the co-discoverer of the structure of DNA, called this the end-replication problem.

But not all cells follow Hayflick's limit and die. Cancer cells, for example, are immortal. They continue to divide over and over again in people and in the laboratory. If, like mortal cells, their DNA is getting shorter and shorter with each round of replication, how do they do that? The answer is an enzyme called telomerase. The end of the DNA that doesn't get reproduced is called a telomere. Cancer cells solve the problem of DNA shortening with telomerase, which goes back and reproduces the tail end of the DNA that the DNA polymerase missed. Scientists are now investigating the role of telomerases in prolonging the life of normal cells, perhaps as a step forward in our hunt for immortality.

 

H
OLLYWOOD MENTIONED THE
H
AYFLICK LIMIT AND ALSO ADDRESSED
the problem of immortality in the 2004 movie
Anacondas: The Hunt for the Blood Orchid
. The story begins in New York City with several pharmaceutical company executives listening to a presentation by research scientists. The scientists describe a rare orchid found only in Borneo:
Perrenia immortalis
, the blood orchid. The orchid, it appears, has miraculous powers. The following exchange takes place:

Get your asses down to Borneo.

The researchers go to Borneo and, for the most part, get eaten one by one by incredibly large, mobile anacondas. (Immortality apparently has a price that even Hayflick hadn't considered.)

In the end, Hayflick concluded, “My goal is to live until the age of one hundred and drop dead on my hundredth birthday with full cognitive and physical abilities.”

 

A
LTHOUGH
S
TANLEY
P
LOTKIN SHARED A LABORATORY WITH
L
EONARD
Hayflick, he didn't share Hayflick's interest in understanding immortality. He was interested only in making a vaccine. So Plotkin took cells from Hayflick's aborted fetus and infected them with rubella virus. Rather than grow the virus in cells maintained at normal body temperature—98.6 degrees—Plotkin grew it at 86 degrees. After twenty-five consecutive passages, the virus grew well at lower temperatures but poorly at body temperature. Plotkin had his vaccine. When he tested it in thousands of people, he found that it induced better and longer-lasting protection against rubella than did Hilleman's modification of Harry Meyer's vaccine. (Although we'll never know, it would have been interesting to determine whether Hilleman's original Benoit strain of rubella vaccine—the one he abandoned at the request of Mary Lasker—was comparable to Plotkin's vaccine.)

Plotkin knew that his vaccine worked and that it was safe. But his choice to use human fetuses would soon meet stiff opposition from an unexpected source: Albert Sabin, the man who had beaten Hilary Koprowski to develop the first live, weakened polio vaccine. Like Salk, Sabin was the son of Russian Jewish immigrants, but unlike Salk, Sabin was mean-spirited and occasionally vindictive. By the late 1960s, Sabin was a well-known and influential scientist. His polio vaccine had replaced Salk's and was well on its way to eliminating polio from the Western Hemisphere.

Sabin worried that the fetal cells Plotkin had used to make his rubella vaccine would become cancerous and that they might harbor dangerous human viruses. Plotkin remembers his showdown with Sabin: “In February of 1969, a three-day meeting on rubella vaccines was held on the campus of [the National Institutes of Health] in Bethesda, Maryland. The meeting was attended by a packed house of hundreds of interested parties, including Albert Sabin. Although Albert had not himself worked on rubella, he was there as a guru. As the meeting progressed, I heard that Sabin had made a number of statements in private deprecating the use of [my vaccine]. The last morning of the meeting there was even an interview in the
Washington Post
in which that opinion was stated. Finally, toward the end of the meeting, Sabin rose to inveigh against [my vaccine] in his rabbinical style, darkly alluding to some unknown agent that might be lurking there. But he didn't have any evidence. It sounds theatrical, but I remember that these words from the Bible came into my mind: ‘The Lord has delivered him into my hands.' After he sat down, I took the microphone and criticized his statements one by one and at length, pointing out that they were strictly
ex cathedra
and without a factual basis. Much to my surprise, I received a thunderous ovation. The great thing about science is that authority doesn't hold sway. Eventually scientific studies will be the deciding factor and outweigh prevailing opinion. Science is always self-correcting. Today's heresy becomes tomorrow's orthodoxy.”

Hilleman later persuaded Merck to replace his modification of Meyer's rubella vaccine with Plotkin's vaccine. “Sometime in 1978, I believe, I was sitting in my office when the phone rang, and it was Maurice Hilleman,” recalled Plotkin. “Maurice said that Dorothy Horstmann [a Yale University researcher] had convinced him that it would be a good idea to replace his vaccine with mine. After recovering my faculty of speech, I readily agreed.”

During the development of their rubella vaccines, Hilleman and Plotkin shared the same fear: namely, that their vaccines would be given to women who didn't know they were pregnant. Since 1969, thousands of pregnant women have been inadvertently injected with rubella vaccine; many of these women were fully susceptible to rubella and were inoculated during their first trimester of pregnancy. But only one fetus has ever been harmed by the rubella vaccine—probably the single best evidence that both vaccines were remarkably safe.

 

O
N
M
ARCH
21, 2005,
A DREAM THAT IN THE EARLY
1960
S SEEMED
unimaginable came true. The director of the CDC, Dr. Julie Gerberding, held a press conference to “formally and officially declare that rubella has been eliminated from the United States.” Many schools for the deaf are now out of business.

It had been little more than sixty years since Norman McAlister Gregg had first noted that rubella virus caused severe birth defects. As of 2000, about half of the world's countries and territories have used rubella vaccine, all with dramatic results. If the number of countries using the vaccine continues to increase, it's possible that rubella will be eliminated from the world within a hundred years of the discovery of its penchant for attacking unborn children. But for now, rubella virus still harms hundreds of thousands of unborn babies in the world every year.

 

D
ESPITE THE SUCCESS OF THE RUBELLA VACCINE,
P
LOTKIN
'
S CHOICE TO
use cells from an aborted fetus angered pro-life groups. But Plotkin wasn't the only one to use these cells to make his vaccine. Vaccines against rabies, chickenpox, and hepatitis A virus also used them. Before the dust settled, the controversy surrounding fetal cells would lead to official pronouncements by the Catholic Church, rebuttals by prominent researchers, and the persecution of Leonard Hayflick.

A
t the front of the opposition to Stanley Plotkin's rubella vaccine stands Debi Vinnedge, director of the Children of God for Life in Largo, Florida: a “pro-life organization focused on the bioethical issues of human cloning, embryonic, and fetal-tissue research.” Vinnedge, a mother of two and grandmother of five, is angry that Plotkin used a human fetus to make his vaccine. “Casually accepting the use of aborted fetal cell lines in medical treatments has been a blatant disgrace to humanity,” she said, “a despicable sullying of the value and dignity of human life, and has lent credibility to the gross commercialization of aborted babies, ripped from their mother's womb so that someone could turn a profit. We must become slaves to the Culture of Death. Using aborted babies as products to help those children fortunate enough to not have their lives snuffed out pre-birth is akin to the most vile form of cannibalism imaginable. Yet we are asked to accept it for every polite reason except one that begs the question: ‘What kind of a civilization have we really progressed to when we can find no better way to protect ourselves than by using the remains of murdered children?'”

Although Vinnedge's words are wildly inflammatory, the logic of those opposed to using a human fetus to make a medical product is clear:

The supreme teaching authority of the Catholic Church—as illuminated by sacred scripture and the teaching of the apostles—is defined in the catechism.

The catechism of the church holds that abortion is intrinsically evil, grave enough to warrant excommunication.

The Vatican and the National Conference of Catholic Bishops have denounced abortion and fetal research.

Therefore, Vinnedge argues, a Catholic, according to his conscience and under the direct teaching of the Catholic Church, has the absolute duty to refuse any medical product derived from an aborted fetus.

Debi Vinnedge knew that Stanley Plotkin's rubella vaccine contained DNA from a human fetus. She simply couldn't allow this DNA to be injected into the arms of children. So on June 4, 2003, she wrote a letter to Cardinal Joseph Ratzinger, then head of the Catholic Church's Congregation of the Doctrine of Faith. Ratzinger was a well-known theologian and prolific author. Today Joseph Ratzinger is Pope Benedict XVI, the 265th and reigning pope.

In July 2005, Vinnedge received a carefully worded response from the Vatican's Pontifical Academy for Life. It wasn't the answer she was looking for. The academy reasoned that those involved with the original abortion had “formally cooperated with evil.” Furthermore, those who used the aborted fetus to make vaccines were engaged in an act that was “equally illicit.” But the doctors and nurses who give vaccines are engaged in only a “very, very remote” form of cooperation with evil, so remote that “it does not indicate any [negative] moral value” when compared with the greater good of preventing life-threatening infections. The Vatican reasoned that parents who refused Stanley Plotkin's rubella vaccine might be responsible for abortions and damaged fetuses caused by rubella. Such parents would be in “much more proximate cooperation with evil” than if they had accepted a morally questionable vaccine.

The National Catholic Bioethics Center, based in Boston, agreed with the Vatican's decision. “Clearly the use of a vaccine in the present does not cause the one who is immunized to share in the immoral intention or action of those who carried out the abortion in the past. Human history is filled with injustice. Acts of wrongdoing in the past regularly rebound to the benefit of descendents who had no hand in the original crimes. It would be a high standard indeed if we were to require all benefits that we receive in the present to be completely free of every immorality in the past.”

But the Vatican didn't let vaccine makers completely off the hook. It emphasized that using an unethical vaccine in no way reflected the church's approval of its production. “The lawfulness of the use of these vaccines should not be misinterpreted as a declaration of the lawfulness of their production, marketing, and use. There remains a moral duty to continue to fight and to employ every lawful means in order to make life difficult for the pharmaceutical industries that act unscrupulously and unethically.” The National Catholic Bioethics Center took the Vatican's warning one step further: “The true scandal here is not that Catholics use these vaccines, but that researchers and scientists who bring us these products do not take into sufficient account the moral convictions of millions of their fellow citizens.”

Because their experiences with abortion were different, Debi Vinnedge and Stanley Plotkin have strongly opposing views. The Catholic Church taught Vinnedge that a child is created at conception and that abortion is murder. Nothing can justify murder. To Vinnedge, the notion that children could be injected with a vaccine that contained small amounts of DNA from an aborted human fetus was unconscionable. Plotkin (who is Jewish) was an infectious disease specialist during one of the worst rubella epidemics in history. He watched rubella virus kill thousands of babies in their mothers' wombs and cause thousands more to be born blind, deaf, and mentally retarded. He spoke with hundreds of mothers who came to his office asking whether they should end the life of their unborn children. Plotkin was shaped by what he saw. He decided to do whatever he could to prevent rubella. “Seeing what I saw about the damage that rubella virus could do to infants,” he said, “I consider the use of [fetal] cells as 100 percent moral. Frankly, I think that our rubella vaccine has prevented more abortions than all the antiabortionists put together.”

Vinnedge doesn't argue with the need to prevent rubella. She argues with the choice of fetal cells to do it. She wonders why Plotkin didn't just use animal cells. After all, Max Theiler used mouse and chicken cells to make his yellow fever vaccine; Jonas Salk and Albert Sabin used monkey cells to make their polio vaccines; and Maurice Hilleman used chicken cells to make his measles, mumps, and pandemic influenza vaccines. All of these researchers made their vaccines by growing human viruses in animal cells. But they were lucky. Some human viruses don't grow very well in animal cells; they grow well only in human cells. Plotkin chose fetal cells to make his vaccine because rubella was one such virus.

But there was another more important reason to use fetal cells: they weren't contaminated with animal viruses. For example, Hilleman found chicken leukemia virus in the measles vaccine that he got from John Enders. Max Theiler's yellow fever vaccine was contaminated with the same virus. But the problem with chicken leukemia virus paled in comparison with what Hilleman found in the late 1950s, when he was interested in making his own polio vaccine—a finding that scared researchers away from animal cells and toward the safe haven of human fetal cells.

 

A
LTHOUGH THEY DIDN
'
T KNOW IT AT THE TIME,
J
ONAS
S
ALK AND
Albert Sabin made polio vaccines that were contaminated with a monkey virus. This particular monkey virus had never been seen before, caused cancer in animals, and had already been injected into millions of children.

To make their vaccines, Salk and Sabin had used kidney cells from rhesus and cynomolgus monkeys, two species that had a long history as research animals. National Aeronautics and Space Administration (NASA) scientists had sent rhesus monkeys into space, and hematologists had used them to define a protein located on the surface of human red blood cells, the Rh factor. Cynomolgus monkeys were also popular among researchers. Behavioral psychologists studied them because they were the only nonhuman primates to wash their food before eating it. And religious leaders worshipped them. Standing in front of the Nikko Toshogo Shrine in Japan are three cynomolgus monkeys, with hands over their eyes, ears, and mouths, representing the religious principle “If we do not hear, see, or speak evil, we ourselves shall be spared evil.” Cynomolgus monkeys are the source of the warning to “see no evil, hear no evil, speak no evil.”

When Salk and Sabin were making their polio vaccines, thirty-nine different viruses had been found in monkeys. Although regulatory agencies were obviously concerned about these viruses, they were reassured by the fact that monkey viruses infected monkeys much better than people and that all of the viruses were completely killed by formaldehyde. But Hilleman wanted to make vaccines that were completely free of monkey viruses. He didn't want to have to rely on formaldehyde to kill them. So in 1958, while attending a conference in Washington, D.C., he called William Mann, director of the National Zoo. Mann invited Hilleman to his home that evening. “He was a very entertaining man,” recalled Hilleman. “I told him about the huge problem that we had with contamination and what it was doing to the whole field of viral vaccines. And he said, ‘Come to my home and meet my Montana wife.' [That night] we went into his living room and I thought that I was in a god-damned African tent with these darts and arrows and masks and voodoo dolls. The place was fully decorated with African artifacts.” Mann explained why the contamination of monkey cells was so common. “The [monkeys] were trapped in Africa and off-loaded at airports, where they would share their viruses,” he said. “They would all be forced together in small spaces, sharing their urine and feces. And employees of the airports, who had no idea of what they were doing, were in charge of feeding and handling the animals. It was a real mess.” But Mann also had the solution. “He told me that I had a simple problem,” said Hilleman. “[He] told me to go to West Africa and pick up African green [monkeys], so-called grivets. There are a lot of them there. Bring them into the Madrid airport. No primates other than human beings come to Madrid. Then put them on a big transport airplane, transport them to New York, off-load them there, and you've got it made.” Using Mann's African green monkeys, Maurice Hilleman was about to discover the fortieth monkey virus.

Hilleman hired a trapper to catch several African green monkeys from West Africa, paid to have them transported to Madrid, and picked them up when they arrived in New York City. When Hilleman got them back to his laboratory, he killed them, removed and ground up their kidneys, placed the kidney cells into laboratory flasks, and examined them to see if they contained any viruses. First, he looked at them through an electron microscope. Nothing. Then he took the kidney cells, disrupted them, and added them to a variety of other cells to see if any viruses grew. Again nothing. Hilleman was satisfied that kidneys from African green monkeys, if freshly caught and directly transported from West Africa, were free of contaminating monkey viruses.

Then Hilleman performed one more experiment. “There was always the nagging apprehension that a culture [of cells] wasn't free of detectable viruses, but how did I know that there wasn't a virus in there that I wasn't detecting?” Hilleman took kidney cells from rhesus and cynomolgus monkeys that had been deemed free of contaminating viruses—cells that were used routinely to make several vaccines—and added them to his African green monkey cells. Soon the cells developed large holes, clumped together, and died. Hilleman reasoned that a monkey virus was killing them. He called the new virus
S
imian
V
irus 40, or SV40.

Next, Hilleman performed a series of experiments that terrified public health officials and within several years made SV40 one of the best studied viruses in the world. Hilleman injected SV40 into newborn hamsters and saw that in 90 percent of them large tumors developed under the skin as well as tumors in their lungs, kidneys, and brains. Some of the tumors weighed nearly half a pound—more than twice the weight of the hamster. Hilleman then found that even though Jonas Salk had used formaldehyde to make his polio vaccine, his vaccine still contained very small quantities of live SV40. At the time of Hilleman's discovery, Salk's vaccine had already been injected into tens of millions of people, and thousands more were receiving it every day. Hilleman also found that Albert Sabin's polio vaccine, which wasn't treated with formaldehyde, was heavily contaminated with SV40. Sabin's vaccine hadn't been licensed in the United States, but it had been given to ninety million people in Russia, mostly children.

In June 1960 Maurice Hilleman stood at the podium of the Second International Conference on Live Poliovirus Vaccines in Washington, D.C. Risking the wrath of Sabin, whom he knew to be in the audience, Hilleman decided to present his data on SV40. Hilleman explained that he had found SV40 in both Salk's and Sabin's vaccines and that SV40 caused cancer in hamsters. Everyone in the room understood the implications of what he had said. In a paper published later that year, Hilleman stated the obvious. “The lack of significant harmful effect in man, in the short term, is well established in results of studies in millions of volunteers fed [Sabin's vaccine] to date. Less can be said concerning a possible long-term effect.” Sabin saw Hilleman's presentation as an attempt to sabotage his vaccine. “I told him that there was no escaping the fact that his vaccine was contaminated with SV40,” said Hilleman. “He went crazy, calling me all kinds of names.”

During the next few years Hilleman and others performed a series of studies that were largely reassuring. Researchers found that although SV40 caused cancer when it was injected into hamsters, it didn't cause cancer when it was fed to them. Sabin's vaccine was swallowed, not injected. Researchers later found SV40 in the feces of children given Sabin's vaccine, but none of those children developed antibodies to it. Apparently, SV40 just passed through the digestive tract without causing an infection. Researchers also found that although formaldehyde used in the making of Salk's vaccine didn't completely kill SV40, it did decrease infectivity at least ten thousandfold. The quantity of residual SV40 in Salk's vaccine probably wasn't enough to cause cancer. But at that point, no one was sure.