Elizabeth Blackburn and the Story of Telomeres: Deciphering the Ends of DNA

by Catherine Brady

But the fabled, much-sought-after Girton College primarily housed undergraduate students and was several miles from the town center, at the opposite end of Cambridge from the LMB, and the college also imposed a strict evening curfew on its student residents. Blackburn, expecting to work late at night in the lab, rebelled at the absurdity of climbing over the college walls to sneak back to her room in the evening. She chose instead to live at Darwin College, a coed, graduate-student-only college, and after she wrote to Girton College to decline its offer, she received a huffy letter of reply, informing her, much to her amusement, that she had forfeited the right to attend a particular sherry party held by the college.

had grown up in the remote highlands of Guatemala, where his U.S. parents worked as missionaries. Like Blackburn, he was disinterested in pop culture and consumed by his scientific work.

The lab was small, Blackburn was not much older than her students, and unlike many primary investigators, she worked at the bench right alongside her lab members. Her disregard for hierarchy shaped an easy intellectual give-and-take in the lab, as Cherry suggested: “Liz was quite young, and she really understood what would help motivate us. She was very open with us.

During her first five years at Berkeley, Blackburn worked ferociously hard, with the ultimate goal of gaining tenure. Not only was she learning how to teach but also she had to learn how to supervise a lab technician, students, and postdocs in the lab, manage the lab operation, engage with her colleagues at Berkeley, and establish her credentials as a researcher, which required active participation in scientific conferences.

When you’ve taken the risk, you have to be very rigorous in showing it’s not an artifact. I think I was more nervous then about publishing something that might be an artifact.”

If Cech had provided the precedent for a catalytic action that relied on an RNA template, Blackburn and Greider’s hypothesis still flew in the face of accepted dogma: a central tenet of molecular biology at the time held that in the essential cellular mechanisms of eukaryotes, enzymes copied DNA into RNA, and never the reverse. The only exceptions found had occurred in then obscure retroviruses, which copied RNA into DNA (hence the term “retro”; HIV later became the most notorious of these viruses), thanks to the action of reverse transcriptase enzymes. Such enzymes were thought to hark back to earlier, more primitive life-forms, and biologists assumed that these enzymes did not exist in more complex organisms, which evolved later, with protein polymerases taking over the role played by RNA in synthesizing the genetic material of the cell. Making Blackburn and Greider’s hypothesis still more risky, reverse transcriptase typically copied thousands of nucleotides at a time in a viral genome. No reverse transcriptase had ever been found to copy only a short sequence of DNA.

Despite the gratification and prestige they bestow, prizes are also problematic. Often, award rules stipulate that only one person may be recognized, perpetuating the image of the lone scientist hero when so much of the research in molecular biology, as in other fields, is as delicately interconnected as the components of an ecosystem. Collaborators may learn from one another and part ways, competitors may spur each other on in ways that enhance their respective research, and in the best case, researchers eagerly share ideas, results, and techniques. Biological research today is also moving toward big-team science—as, for example, in the massive number of collaborators on the human genome project— a reality at odds with the emphasis on individual achievement. Two competitors, approaching the same problem differently, may both arrive at solutions more or less simultaneously, so that it is difficult, if not impossible, to award one of them first place and the other second. As a side effect of the tournament mentality, “junior” collaborators (postdocs or grad students) may fail to receive equal recognition for their role. Conscious that her work on telomerase was a collaboration between equal partners, whenever Blackburn is honored for her work on telomerase, she raises the question of whether the award should be shared with Greider and often insists on the point.

An established primary investigator must function as an intellectual manager as well as a business manager. Primarily, the primary investigator nurtures talent, providing postdocs and graduate students with intellectual capital for their experiments. But the job also demands skill at balancing a ledger, savvy at negotiating the politics of funding and publication, and a taste for civic-minded volunteerism that consumes what little free time remains. Each of these often conflicting responsibilities has to be synthesized with the others; mentoring must somehow translate to the only hard evidence that counts, publication in reputable peer-reviewed journals, and to ensure future funding, the lab must churn out that product with extraordinary efficiency.

Blackburn perceived a significant flaw in this system: “The process favors grants that cannot be faulted—research that seems guaranteed to succeed. The exciting papers you publish aren’t risk-averse, or the work wouldn’t have been done.” Yet she quickly added that a researcher can finesse this liability: “Countering this tendency to support more cautious research is the fact that the grant itself is not a contract.” While a grant may need to be worded adroitly so that it fits within semantic parameters, the research lab can pursue questions beyond the concrete, careful aims laid out in the grant itself.

Though it matters—up to a point—if you publish first, the good paper is the one that will prevail. It will be cited more often, another criterion of the success of a paper, though this can sometimes be a function of herd mentality. So there’s tension between getting a paper out first and wanting to do the best work. There is never a time when it’s perfect to publish. Everything you do raises more questions. So there’s a judgment call—be complete, be sure the paper can withstand scrutiny by expert reviewers who are also your competitors.

The media, like the public, has an appetite for singular events and dramatic discoveries, which often runs counter to the more speculative and qualified truths that science produces in fits and starts. Worse, once an appealing idea takes hold, it becomes difficult to dislodge. Early on in telomere research, a study reporting that human skin cells usually divide eighty to ninety times in culture whereas cells taken from a seventy-yearold man might divide only twenty to thirty times, was viewed as evidence that the maintenance of telomeres might be implicated in the aging process. This “fact” (which even Blackburn and Greider cited in a 1996 Scientific American article) later proved to be an artifact, yet the correction has never entered the mainstream press and is only occasionally quoted in newer reviews.23

The energetic and well-funded participation of biotech companies in cutting-edge biological research can prove dangerous, because unexpected and novel findings that present a commercial liability are exactly the findings that drive pure science. Furthermore, a company’s (natural) interest in profit requires proprietary rights over research, which runs counter to the open exchange of ideas necessary to science. Eager to share in any windfall, universities commonly enter into licensing agreements, or “sponsored projects,” with corporations when research seems close to generating a profitable product. Such sponsored projects often entail a material transfer agreement that preserves a company’s commercial prerogative over any results—and potentially any future discoveries that in any way rely on the patented material. Proprietary rights are dangerously murky in molecular biology, which produces not new inventions but intellectual property, such as gene sequences, with significant medical and social consequences. When such research tools are patented, a company might waive the cost of access for academic scientists, but its commercial interest in any resulting product impedes ready access and can curtail further exploration.

Since its inception, the JSC has made presentations to Congress, advised the Congressional Biomedical Research Caucus (a bipartisan group of congressional representatives), and served other branches of government. According to Marincola, the JSC acquired a reputation as “the premier caucus in Congress for the quality of its presentations and its staying power. Every month for fourteen or fifteen years, we’ve sponsored monthly briefings on the Hill, inviting prominent scientists who gave twenty-minute talks on their research and then answered questions. A lot of congressional staffers tell us this is how they learn about science.”33

Not all of NASA’s claims were true, and the steering committee emphatically countered the agency’s inaccuracies. Perhaps to woo the opposition, NASA invited Blackburn to watch a launch of the space shuttle in Florida from a VIP viewing site. But since no children under sixteen were allowed, she couldn’t bring her twelve-year-old son, who would have adored seeing the launch from close up as much as she would have. If she felt uncertain about whether conscience barred her from accepting the offer, her son’s anticipated reaction settled the issue: “Ben would have killed me if I went without him, and I would have heard about it for years.”

In biology, no lone hero in a garret can come up with the kind of sudden, brilliant insight that lights up the sky in mathematics or physics and instantly offer conclusive proof. Knowledge is instead accumulated and tested in fits and starts, and progress is chaotic and contested.

hundreds of thousands of amino acids.

Error?

Blackburn’s scientific thinking has a cyclic nature, something like contraction and dilation. Prescott remarked her skill at “asking a very pointed question in a way that will give you an answer, whether expected or not,” and also recalled that she had “very strict standards of proof”; if he brought her unusual results, “it often took a few experiments to convince her.”34 Yet Blackburn’s skepticism has qualities of radicalism as well as conservatism. Given her intimate familiarity with different model systems and her alertness to anomalies, she can fluidly transition from a narrowly constricted, descriptive mode to a risk-taking stance—a seemingly prescient leap to a new or revised model.

And if a lab is like a business, it also has much in common with a medieval craft guild: the value of the work is collectively determined by guild members, who rise through the ranks in a series of steps designed to demonstrate mastery. Those who become masters are obligated to teach their trade, but graduate students and postdocs, the underpaid apprentices of research science, are vulnerable to exploitation and at the same time eager to claim individual credit for their work. Conducting scientific research requires the same odd combination of repetitive work and inspired creative effort once demanded of an apprentice medieval craftsperson whose assigned rote task might ultimately constitute a component of a work of art. The same graduate student who must dump out a box of toothpicks before sterilization and sort them in a jar with their broader tips down (so that he won’t poke holes in the soft plate when streaking yeast cells) must also be capable of making sound inferences based on the data the experiment nets. Like members of a medieval craft guild, lab members are motivated by altruism as well as ego: ambition coexists with a collective investment in discovering answers to questions that will expand scientific knowledge.

When Gilley visited the lab, Blackburn put him up at her own ” house. Like Prescott, Gilley was impressed by Blackburn’s lack of pretension—”There I was just showing up at the doorstep of this really famous person I’d idolized and read about during my previous training”—and he also immediately registered that “she doesn’t really separate her personal and professional life”:

Most established primary investigators don’t work at the bench, but Blackburn did so for much of her career.

To Blackburn’s surprise, Kass seemed eager for her to join the council and minimized any difficulties that might arise in nominating someone who was not a U.S. citizen. Only later would she learn that Kass had approached a number of scientists before he spoke with her, and “knowing his views, they had turned him down.” In their initial conversation, Kass assured Blackburn he wanted the panel to represent diverse opinions and would not force consensus.

Only by a rather questionable analogy could this attempt to correct a superficial imperfection be equated with the search for cures for devastating illnesses such as Alzheimer’s disease. Blackburn found it disquieting that “a Gothic horror story, patently about a mad scientist, was seriously considered as having something to do with sober national policy.”

Blackburn’s encounter with Washington politics exemplifies the tension between the scientific ideal of a strictly defined truth and the more ambiguous context in which public policy is generated. Such tension contributes to the vitality of a pluralistic democracy because it fosters debate rather than foreclosing it, but debate founders when evidence is treated as if it were as malleable as opinion.

Her lifelong preference for working in an academic environment rather than a biotech company stems from a similar resistance to pursuing work for the sake of a predefined goal: “I don’t want anybody to be telling me what to do. In clinical research, there’s a goal and only one answer: it works. To me, that’s technology, and I don’t find that kind of goal-oriented problem solving as interesting to do, though I want it to be done. It would be great if that’s the outcome of this research, but it’s not my excitement. In the process of doing work that may turn out to provide useful therapy, we’re learning how cancer cells are responding, and that’s what really interests me. Logically speaking, if this was all about the goal, you’d focus on that and nothing else. But you’d be crazy not to look around to try to understand what cells reveal.” Lateral thinking—“looking around” rather than focusing on a narrowly defined goal—is essential to Blackburn’s definition of intellectual scientific inquiry.

She is no lone hero but a highly collegial and collaborative citizen of an interactive community, someone whose idealism does not contradict her competitive spirit.