Across the country in his lab at the Sidney Farber Cancer Institute in Boston, a young Harvard Medical School professor named Jack Szostak had been struggling to understand how a very different single-celled organism, the humble baker’s and brewer’s yeast, handled broken bits of DNA. When Szostak inserted linear, lab-manufactured DNA strands, unprotected by telomeres, into the yeast, the DNA was either inserted into a chromosome or completely destroyed. Or, occasionally, the two ends of a strand would be joined together to form a circular bit of DNA. Szostak’s pieces of DNA never survived as linear strands, for unlike naturally occurring chromosomes, their ends weren’t protected by telomeres. Then Szostak heard Blackburn discuss her work at a conference in the summer of 1980. He approached her, and during an intense discussion the pair came up with what Szostak later recalled as a “wild idea.”24 They would graft Tetrahymena telomeres onto the end of Szostak’s lab-created mini chromosomes and insert them in yeast. Just maybe the grafted-on telomeres would protect Szostak’s chromosomes.
Blackburn and Szostak found their long-shot hunch confirmed. The mini chromosomes with their grafted-on telomeres were not degraded. Somehow that six-letter repeating sequence of DNA in the Tetrahymena telomeres was protecting the chromosome ends, even in a very different organism. (It’s now known that in humans and other mammals the specific DNA sequence of telomeres attracts a group of proteins—appropriately named “shelterin”—that form a cap at the fragile chromosome end, preventing the cell from “thinking” that it is an open, broken end and trying to repair it, a process that can end in cell suicide if the repair work fails.)
Blackburn and Szostak published their findings in the eminent journal Cell in 1982.25 Now another question presented itself. The end-replication problem dictated that the yeast telomeres should get shorter and shorter with each division, until they were gone and essential DNA began to be lost. In a single-celled organism, this wasn’t compatible with survival. An organism of just one cell, like yeast, had to be able to replicate infinitely, or perish. Such organisms must have some mechanism for fighting back against the end-replication problem. Soon after, working with Blackburn’s graduate student Janis Shampay, Blackburn and Szostak demonstrated that in yeast the telomere ends were being extended with additional tiny DNA snippets while they replicated.26 In effect, the cells seemed to be “trying” to maintain their telomeres at a roughly constant length.
The scientists proposed that there might be an enzyme capable of lengthening chromosomes at their tips by adding those small, repetitive snippets of DNA. This enzyme would have to work quite differently from DNA polymerase, the powerful enzyme that replicated the whole of a cell’s DNA during cell division—except for that troublesome end bit—but which required a DNA template from which to copy.
On Christmas Day 1984 Carol Greider, a twenty-three-year-old PhD student in Blackburn’s Berkeley lab, peered at a newly developed X-ray film and saw something that seemed like it was too good to be true.27 It was the first hard evidence that a telomere-lengthening enzyme existed. It showed up in a series of neat bands that climbed, ladderlike, up the X-ray film. The regularity of the bands made it clear that the putative enzyme was adding six-base snippets of DNA—telomeric repeats—to the telomeres in a test-tube mix that Greider had made, containing synthetic telomeres and extracts of Tetrahymena cells.28 (After further experiments confirmed that her seemingly too-perfect findings were in fact real, Greider went home and danced to the whole of Bruce Springsteen’s Born in the U.S.A.)
It would be 1990 before Blackburn and her colleagues at Berkeley definitively demonstrated the enzyme’s activity in a living organism.29 By then it had been given a name: telomerase. It was a complicated, unusual enzyme, and Greider and Blackburn had shown that it carried its own template of genetic code, allowing it to affix itself to the end of the chromosome—the bit that DNA polymerase can’t manage to duplicate—and begin adding genetic sequence in the form of the telomeric repeats specific to that species.30
How does all of this circle back to Hayflick’s fibroblasts aging in their bottles half a century ago? It would take a conversation between Greider and a scientist named Calvin Harley, at McMaster University in Hamilton, Ontario, to finally connect those dots. Greider often traveled from Berkeley to McMaster to visit her boyfriend, Bruce Futcher, who shared a lab with Harley, a mustachioed, mild-mannered Canadian who had been fascinated with aging since he was a boy.31
It was Harley who told Greider about an obscure theory that she had never heard of. It had been proposed back in 1971 by a young Russian who had an epiphany in the Moscow subway. Greider learned about Alexey Olovnikov’s theory that cells hit the Hayflick limit because of the end-replication problem—the cells finally stopped dividing when they somehow discerned that more divisions would begin to eat into their critical, life-directing DNA. Olovnikov had not had the tools to test his theory almost two decades earlier. But in 1988 the human telomere sequence—TTAGGG—was discovered.32 Greider, who had completed her PhD and taken a position at the Cold Spring Harbor Laboratory on Long Island, New York, heard of the discovery early, at a conference, and called Harley with the news. She, Harley, and Futcher now had the means at hand to find out if Olovnikov had been right. They could ask and answer the question: what happens to the length of human telomeres over time?
They grew fibroblast cells that had been derived from several types of human tissue: fetal lung tissue; newborn skin; and skin from adults aged twenty-four, seventy-one, and ninety-one years. As the cells replicated, the scientists regularly measured the length of their telomeres. No matter what their starting lengths—and the fetal and newborn cells had substantially longer telomeres to begin with—all of the cells’ chromosome tips grew progressively shorter with time. On average their telomeres were clipped of two thousand DNA letters before they died, or roughly fifty letters each time the cells divided. The findings comported beautifully with the end-replication problem and left the cells with, on average, about two thousand letters in their telomeres when they finally stopped dividing—an amount, the scientists inferred, that could be merely a nonfunctional stub. Their findings “could be biologically significant,” the three biologists wrote, with typical scientific restraint, in the 1990 Nature paper that reported on the experiment.33
Why didn’t telomerase “save” the cells in this experiment, protecting their telomeres by adding to them to maintain their lengths? The answer had to be that telomerase was not active in all human cells. And in fact other scientists would soon demonstrate that telomerase is lacking in most human cell types.
With the publication of the Harley-Futcher-Greider paper, a simple, elegant concept captured the public imagination: telomeres in effect burn down, like a candle wick, until the end is reached, the light goes out, and the cell stops dividing and, finally, dies. The notion was a tantalizing and seductive one, not least for questers after the fountain of youth. For it wasn’t unthinkable that what happened in a test tube might happen in the human body: that the ravages of growing old, from sagging skin and thinning hair to all manner of age-related diseases, resulted from the clipping down of our telomeres; and that telomerase might rescue humanity from all of that. That notion, Blackburn later told the writer Stephen Hall, “was a lovely idea—so simple that nobody but an idiot would believe it.”34
This did not dissuade the enthusiastic. In 1990 a company called Geron was established in Menlo Park, California, to chase the promise of telomerase in battling aging. The scientists at Geron were keenly aware that Harley, Futcher, and Greider had demonstrated a correlation between telomere shortening and cellular aging but that, as the trio themselves pointed out, their findings did not establish that the shrinking telomeres caused cells to become elderly. A few years later the Geron scientists, working with Hayflick’s former graduate student Woody Wright and his group at the University of Texas Southwestern Medical Center at Dallas, conducted an experiment designed to reveal whether telomere shorte
ning caused cells to age. They added telomerase to two kinds of cells: fibroblasts from human foreskin and from specialized cells that line the retina in the human eye. They also kept control cultures of each of these cells, without telomerase added.
The control cells proceeded to divide to their Hayflick limit, take on the appearance of elderly cells, and stop dividing. Those with the telomerase did not. On the contrary, they flourished, maintaining long telomeres, dividing prolifically well beyond their Hayflick limit, and yet maintaining normal chromosomes; these were not cancer cells that had somehow bypassed the normal brakes on cell division. By the time the resulting paper went to press, the telomerase-rich cells had exceeded their normal number of replications by at least twenty doublings. The scientists had established beyond doubt a causal relationship between telomere shortening and the aging of cells in the lab. The new paper, published in Science in 1998, had an eye-grabbing title: “Extension of Life-span by Introduction of Telomerase into Normal Human Cells.”35
A media frenzy followed. The New York Times splashed the news on its front page, then ran two more articles in the space of six days.36 “I didn’t think I’d live long enough to see this,” Hayflick told the San Francisco Chronicle in another front-page article.37 The price of a share in Geron rose from $7.80 on the last day of 1997 to $12.70 on January 16, 1998, the day the Science paper was published. Twenty months later, as the price still hovered around $11.00, Fortune observed that “the bold little company has achieved the highest buzz-to-equity ratio in biotech history.”38 But the story turned out to be commercially disappointing. In the summer of 2016 the twenty-six-year-old Geron had yet to win FDA approval for a single product and had abandoned its attack on aging for an attack on cancer. Its stock was trading at less than $3.00 per share.
The relationship between telomeres and aging has emerged as immensely complex. The running-down of telomeres in cells in the lab does not translate as the simple, unitary cause of the aging of entire organisms, including human beings. For one thing, unlike cells in culture that grow to their Hayflick limits and then stop dividing, most of the cells in our bodies divide rarely. These cells probably do not come close to running down their telomeres in the course of our life spans—something that Hayflick’s work with those specimens from multiaged cadavers back in 1965 pointed to quite clearly. (Remember the lung cells from the eighty-seven-year-old cadaver that divided another twenty-nine times in culture?) What’s more, we now know that the aging of our cells is also likely mediated by mechanisms that can bypass telomeres entirely, like chronic inflammation and something called oxidative stress, in which toxic by-products of cellular metabolism directly damage proteins and other cell components.
Nonetheless, a group of patients with rare, inherited genetic disorders have provided important evidence of a direct effect of telomere length on aging in living human beings. People with these disorders, which have been collectively dubbed “short telomere syndromes,” have very short telomeres and suffer from a characteristic set of age-related degenerative diseases.39 Often these diseases make themselves manifest in cells that, unlike most, divide frequently, like the stem cells in organs that repair and maintain them in the face of wear and tear, or the stem cells in bone marrow that give rise to billions of blood cells each day. For instance, one disease that appears in people with short telomere syndrome is aplastic anemia, a condition in which the blood cell–manufacturing cells in the bone marrow fail and the numbers of all kinds of circulating blood cells fall dangerously low.40
Is the converse then true? Do long telomeres bode well for health? Some tantalizing findings have suggested as much. One particularly striking study of scores of healthy centenarians showed that both they and their offspring maintained longer telomeres as they aged, compared with subjects of ordinary longevity. It also showed that longer telomeres were associated with better mental functioning, healthy levels of blood fat, and fewer age-related diseases.41 However, this study did not establish cause and effect. It simply showed a correlation.
Importantly, telomerase has been implicated in cancer. The scientists at Geron—along with other groups working elsewhere—showed that in stark contrast to most normal cells, telomerase is active in cancer cells. Working with Wright and his colleague Jerry Shay at the University of Texas Southwestern Medical Center at Dallas, they measured telomerase activity in 101 biopsies from human cancers and in 50 biopsies from normal human tissues. Telomerase was active in 90 of the cancer samples and none of the normal ones.42 After their paper was published in Science in 1994, research on the role of telomerase in cancer skyrocketed.43 Recent findings include several papers showing that in families with inherited mutations that kick telomerase into high gear, the risks of malignant melanoma (a skin cancer) and of glioma (a brain cancer) are elevated.44 Biologists have also found evidence that a cell’s ability to shut down its own division—to short-circuit itself into a post–Hayflick limit, nondividing state—may have evolved as an essential defense against cancer.
Like the complex role of telomerase in cancer, the relationship between telomere shortening and aging is still being studied intensively today. We now know that there are a variety of influences, internal and external, on telomere length that make it clear that telomeres aren’t like wind-up clocks that start ticking when we are in the womb and march in lockstep toward a predictable, predetermined finish line. Heredity plays a role: some of us have the good fortune to inherit longer telomeres than the average human being. So do environmental exposures.
Today biologists are probing basic questions like these: What exactly tips telomeres from being dangerously short into being nonfunctional? What precisely happens to them, at the molecular level, as they hit the Hayflick limit? And when this happens, what complicated symphony of cellular signaling actually causes the cell to stop dividing? Each new answer they find opens up an ever-deeper set of questions.
In December 2009 in Stockholm, King Carl XVI Gustaf of Sweden presented Blackburn, Greider, and Szostak with the Nobel Prize in physiology or medicine for their discovery of how chromosomes are protected by telomeres and of the enzyme telomerase.
Hayflick had described a phenomenon. The Nobel trio had explained it.
CHAPTER TWENTY-SIX
Boot-Camp Bugs and Vatican Entreaties
Largo, Florida
Naval Station Great Lakes, Illinois
Cleveland, Dayton, and Centerville, Ohio
1999–2012
I am fond of saying that rubella vaccine has prevented thousands more abortions than have ever been prevented by Catholic religionists.
—Stanley Plotkin, June 27, 20131
In 1999 Debi Vinnedge, a forty-four-year-old grandmother living in Clearwater, Florida, founded a nonprofit group called Children of God for Life to advocate against human embryonic stem cell research. Scientists had announced the isolation of the versatile cells only one year earlier and they were very much in the news. Because they can grow into virtually any cell type, it was hoped that they could be used to grow cells and organs to replace diseased ones. The cells are obtained from days-old embryos left over at fertility clinics, destroying the embryos in the process. The cells’ origins bothered Vinnedge greatly. She was a devout cradle Catholic and abhorred the destruction of human life at any point after conception.2
But soon after launching Children of God for Life, Vinnedge stumbled on an article in her local diocesan newspaper that caused her to turn her focus away from human embryonic stem cells. It asserted that several childhood vaccines used in the United States were produced using cells from two fetuses aborted decades earlier. She began reading everything she could find about the vaccines. The more she learned, the more distressed she became.
Vinnedge was a grandmother of two, and she soon figured out that both her children and her grandchildren had been vaccinated with Merck’s MMR II vaccine, the only one available in the United States—and that the rubella component ha
d been made using WI-38 cells. (Her children, born in 1975 and 1977, had received booster shots of Merck’s MMR II vaccine in the 1980s.) As a young mother she had had no idea that fetal cells were used to make the vaccine, and this made her angry. She also learned that the company made the individual components of the MMR vaccine as separate vaccines, meaning that people who objected to the fetal origins of the rubella vaccine could boycott it but still vaccinate their children against measles and mumps.
This was something, but it was not a long-term solution in Vinnedge’s view. It left children unprotected against rubella. She learned that in Japan the Kitasato Institute made what she calls an “ethical” rubella vaccine, growing the virus in rabbit kidney cells.3 Similarly, another Japanese company made a hepatitis A vaccine, as Merck was now doing using MRC-5 cells, without using fetal cells.4 She wrote to Merck expressing her concerns and asking it to drop the fetal cell–manufactured injections and replace them with animal cell–propagated alternatives. The company ignored her first two letters but responded to a third. In that response Isabelle Claxton, the company’s executive director of public affairs, noted that both WI-38 and MRC-5 came from two legal abortions in the 1960s that were not undertaken with the intent of producing vaccines. No new abortions would be needed, now or in the future, for Merck to continue production, she added. “We use these cell lines because they are the best science has to offer in terms of producing a safe and effective vaccine against certain diseases.”5
Not satisfied, Vinnedge, with support from the Catholic Medical Association and another antiabortion group, Human Life International, bought the requisite stock in Merck—$2,000 worth—and developed a shareholder resolution. It proposed that, because Merck was “materially benefiting from the destruction of human life,” a special committee of the company’s board be formed to link executive compensation to the company’s “ethical and social performance.”
The Vaccine Race Page 43