Capping the Chromosome: Elizabeth Blackburn and the Discovery of Telomerase (Women in Science 59)
Telomerase is one of those enzymes which just won’t let you come to a settled opinion. When it runs wild, it promotes cancer. But it also protects each and every one of your chromosomes faithfully, ensuring that your cells don’t hurl themselves into an early death. It can be an evil little fellow, but we can’t live without it, and for the details on all that fascinating complexity we have the Tasmanian born Nobel Prize laureate Elizabeth Blackburn (b. 1948) to thank.
There was a time, and not long ago, when we quite happily knew nothing about the ends of chromosomes. Sequencing was a laborious process, and hardly anybody was in the business of applying its early techniques to what lay at the extremes of a chromosome. And yet, it was precisely here that some of the most dramatic genetic activity was to be had since Barbara McClintock had hypothesized jumping genes. When Elizabeth Blackburn first started posing questions of the chromosomal ends in 1975, she was taking a step that would define the next forty years of her life and contribute fundamental insights into cancer, aging, and the astonishing variety of components involved in normal cellular replication and maintenance.
Blackburn grew up in a household that expected excellence and a society that promoted fundamental modesty. She was born in the tiny bush town of Snug in Tasmania, and spent her formative years in Launceston where her father practiced medicine. Her mother was also medically trained, and worked as much as the raising of seven children and the management of an alcoholic husband allowed. Elizabeth was given the best education possible under the circumstances, including classes in elocution, piano, violin, and drawing, all of which she excelled at.
Brought up in another culture, young Elizabeth might have become insufferably conceited, but the reigning paradigm in Tasmania was “mateship” – to treat everybody with equal regard and respect, a quality that Blackburn would eventually infuse into her laboratory, creating an island of camaraderie and anti-hierarchy that attracted some of biochemistry’s brightest young minds.
In high school, she was drawn to the neatness of biochemistry, the precision with which it proposed its questions and sought its answers. She doodled amino acid structures on paper in her daydreamy moments the same way the rest of us doodle TIE fighters or little piles of poo.
When her parents separated, money for private schooling dried up, and Blackburn threw herself twice as hard into studying so that she could earn a scholarship to a good university and distract herself from the grinding reality at home. Studying biochemistry at the University of Melbourne, she was one of those students who unaccountably actually spends most of their time studying the field they purport to be interested in. Her solid lab work and flashes of brilliance earned her a spot as a PhD student in Fred Sanger’s Laboratory of Molecular Biology in Cambridge, which was THE place to be in 1971 for a student interested in molecular genetics.
Sanger’s team specialized in the developing methods of DNA and RNA sequencing. They sought to discover the amino acid sequences of interesting proteins and to use that sequence to build theories about how the protein built itself three dimensionally. Armed with little more than digestive enzymes that snipped DNA into smaller parts and the blind determination to push through the massive task of organizing the resulting bits in a plausible sequence, Sanger’s lab was renowned for the solid rigor of its methods, which Blackburn perfected while studying bacteriophages. That training proved to be just what she needed to get a job at John Gall’s lab at Yale, where from 1975 to 1977 she was set to work to use her sequencing know-how to plumb the mysteries of the end sections of chromosomes.
Gall is one of science’s undisputed good guys. He vociferously championed the recruitment and support of women in the sciences, and made his lab a place of mutual support and intellectual stimulation. Lab technicians, postdocs, and senior scientists were all encouraged to communicate with one another freely, to share and aid rather than to hide results and compete. Blackburn, set the task of investigating the tiny ribosomal DNA of Tetrahymena, produced novel, paradigm-shattering results almost from the word go.
She found that, upon replication, rDNA has a tendency to change its length, sometimes getting longer, sometimes shorter, a result which worked against the notion of chromosomal stability that was at the heart of what we thought we knew about genetics. She also found that, at the ends of these chromosomes, there was an odd pattern, a sequence of four C’s followed by an A, repeated many times for no discernible reason. Using radioactive marking, she had confirmed by 1976 that this pattern was found on both ends of her rDNA, repeatedfifty times, and hypothesized that rDNA’s variable length was due to differences in the number of these strange end repetitions.
It was puzzling. Weird. Why would nature, which is usually so economical with its resources, waste so much space on every single chromosome with… nonsense? Blackburn had hit upon one of the strangest areas of chromosomal activity, and for every radical discovery she would make in the next twenty years, another three profoundly puzzling genetic attributes would announce themselves.
In 1978, Blackburn was hired to start up a lab at UC Berkeley, where she promptly set herself the task of explaining what caused these sections of repeating units, called telomeres, to change their length. She first proved that telomeres were not unique to Tetrahymenaby finding them in another organism, the ciliate Glaucoma. Having established that this strange chromosomal feature was more than just the fluke of a single species, she sought the mechanism of telomere lengthening, and radically hypothesized an enzyme that somehow had the ability to (a) recognize when a telomere needed lengthening, (b) recognize where in the pattern a telomere was, and (c) add additional bases that kept the pattern going.
Blackburn began the hunt in 1984 with Carol Greider, a second year PhD student who chose Berkeley over Caltech just to have the chance to work with Blackburn. Together, they attempted a series of assays that aimed to catch their proposed enzyme in the act of adding to the telomeres. On Christmas Day, 1984, Greider developed the image that brought telomerase to the world, an enzyme that, they would argue, worked like nothing else that biology knew of.
They believed that this telomere-building enzyme was made up of proteins surrounding an RNA template, a template that could latch onto the telomere end nucleotides, lining up precisely with the repetitious pattern, and featuring enough overhang on which to place more DNA bases, thus extending the sequence. Molecular biology held that this was plainly impossible, that DNA made RNA, but that RNA never made DNA. It would take a decade of experiments and argumentation for Blackburn and Greider, but their model of a reverse transcriptase enzyme with an RNA template at its core eventually became a central model in modern genetics, explaining with tantalizing physical simplicity the mystery of telomeric extension.
Blackburn and Greider’s papers in the Eighties found and described telomerase, and other biologists had found that, when a cell lost the ability to produce telomerase, its cells got shorter and shorter with each replication until finally they just refused to continue division and died. This solved the long-standing mystery of genetics: Why don’t chromosomes shrink? Because of how DNA polymerase works, it will always leave out a few bases at the 3’ end of each chromosome it copies, meaning that, each replication, the daughter chromosomes should be a BIT shorter than the parents. The action of telomerase, lengthening each strand before the copying stage, compensates for the shortening, and explained the riddle at last. Telomeres, which a decade earlier hadn’t even been a thing academically, were suddenly a hot topic as popular culture picked up on the associations of telomere shortening with aging and cell death and leapt to the conclusion that telomerase might be a mystical elixir of youth.
Meanwhile, Blackburn moved her lab to UCSF where she set her team to figuring out precisely how the protein and genetic components of telomerase worked together, and how the cell maintained a proper balance between telomerase’s overactivity, which resulted in cancer, and its under-activity, which lead to shortening chromosomes and ultimately cell death. They found that telomerase not only lengthened telomeres, but protected them as well, providing a cap that guarded the chromosome from being sliced up by nuclear enzymes and from being joined to other pieces of DNA by ligases. They found a whole family of proteins that worked together, clamping and unclamping from the DNA strand to alternately block and grant access to the telomere, and worked on therapeutic cancer techniques that would hinder excessive telomere activity while preventing critical chromosome shortening, with many promising results.
But none can escape administration, and Blackburn found herself, as the founder of an entire field of genetic study that was being hotly pursued by the rising bioengineering corporations of the 80s and 90s, to play an ever more public role. She directed a department at UCSF for five years at a time when the number of female directors and deans could be counted on one hand and, more publicly, agreed to serve on George W. Bush’s Advisory Commission on Bioethics. It was a panel of deeply conservative thinkers tasked with legitimizing the President’s ban on stem cell research. The odds were stacked against any scientist attempting to argue from data rather than political positioning, but Blackburn felt that, if somebody responsible didn’t represent the scientific community, a lasting harm could be done, both to the scientific community, and to the health of humanity. It was a frustrating, doomed battle, but in waging it Blackburn brought science’s case for therapeutic stem cell research to the American people, and threw an effective kink in the administration’s plans to trammel biological research uncontested.
Award and honors came, as they must, including the little matter of winning the Nobel Prize in 2009, but, typical of her mateship approach to life and work, Blackburn never allowed herself to get hung up on the adulation, but devoted her energies instead to mentoring the members of her lab and providing a place where rigorous experimentation and inspired whim could come together. And the work on telomeres and telomerase continues, probing their relation to disease and their potential to help humans avoid its ravages. For those who think that, to be a titan of science, you have to be a raving egomaniac or a dictatorial control freak, she is the great exception. Let her reign be long.
FURTHER READING: Elizabeth Blackburn and the Story of Telomeres (2007) by Catherine Brady is basically the book. It will tell you everything you need to know about everybody who did anything that had anything to do with telomeres between 1975 and 2005. The sense you get about Blackburn from the book is that she is her work – there’s a husband who pops up every hundred pages or so, and a kid likewise, but overwhelmingly, it’s the work, and if you’re curious about how academic research science happens in the modern age, this book documents its vicissitudes intimately. I don’t like how the link between the 5th carbon and phosphate is drawn in the DNA molecules, and the cover layout puts you in mind of nothing so much as a pamphlet you get in your doctor’s office about nasal steroids (it bothered me so much I eventually had to hide it in a part of the room I can’t see from my desk), but it’s a deep tale of somebody whose work deserves deep telling.