Untying Nature's shoelaces
Fans of crosswords and pub trivia might be familiar with the word ‘aglet’ – the technical name for that funny bit of plastic or metal at the end of a shoelace that stops it from fraying. What you might not know is that every single one of our chromosomes also has the biological equivalent of aglets – more formally known as telomeres.
Although they’re made of DNA and protein, these molecular aglets do pretty much the same job as their shoelace equivalent. Chromosomes in very simple organisms like bacteria are circular, so there are no loose ends. But the chromosomes in every complex organism from yeast upwards are long strands of DNA, with two ends.
Cells don’t like loose DNA ends, which are usually created when DNA gets damaged and broken, and will try and glue them back together again. But if a cell starts gluing random chromosome ends together, it’s going to get in a big mess very fast.
Since the late 19th century, microscopists knew that chromosomes were long strings (although exactly what they were made of was still a mystery). By 1911, fruit fly geneticist Thomas Hunt Morgan proposed that they were effectively strings of genes in a particular order, with a beginning, middle and end. And it was his student, Hermann Muller, who first coined the term ‘telomere’, from the Greek words for ‘end’ and ‘part – that’s telos and meros.
But one of the first people to really look closely at telomeres was plant geneticist Barbara McClintock – yes, it’s her again – who was looking at the chromosomes in maize corn kernels down her microscope, noticing distinct ‘knobs’ at each end. She also figured out that these natural knobby ends behaved differently from broken chromosomes, so must have some kind of special molecular protection.
Later on, she also figured out that there must be a specific enzyme responsible for ‘healing’ these ends, as she put it. This was a prescient insight, as we’ll soon find out.
The next big step came in the late 1970s. Fresh from her PhD with Fred Sanger in Cambridge, who had just invented a revolutionary method for sequencing DNA, a bright young scientist named Liz Blackburn headed over to join the lab of Joe Gall at Yale University in Connecticut.
She quickly put her sequencing skills to good use, focusing on some unusual chromosomes in a small, hairy single-celled organism called Tetrahymena thermophila. She found that all of them had the same sequence at each end: TTGGG, repeated around 50 times.
Other researchers found a similar arrangement in a different unicellular species, suggesting that these strange repeated telomere sequences might actually be A Thing. But these little organisms had pretty weird chromosomes, so it wasn’t until Blackburn and her collaborator Jack Szostak discovered that yeast chromosomes are all capped with a repeated sequence too, albeit one that’s slightly different from Tetrahymena, that it did turn out to be A Thing after all.
More impressively, they also showed that the Tetrahymena sequence could sub in for the yeast one, suggesting that telomeres might work in the same way across all species.
The discoveries began to come thick and fast. By the mid-80s, Blackburn was now running her own lab at Berkeley in California, and had recruited a talented PhD student, Carol Greider. Together, they discovered that the ends of chromosomes aren’t copied in the same way as the rest of the genome but have their own special enzyme, which they called telomerase.
Even more strangely, this enzyme was mostly made of RNA – a single-stranded DNA-like molecule – which it uses as a template to make more telomeres. By 1988, other scientists had unravelled the repeated DNA sequence in human telomeres – TTAGGG – unearthing the human telomerase enzyme a year later.
The discovery of telomeres and telomerase netted Greider, Blackburn and Szostak the 2009 Nobel prize in physiology or medicine – the only time to date that two women have won a science prize in the same year.
By this time, the field of telomere research was a burning hot topic – not just because they’re cool and interesting in their own right, but because of the connection to cancer (and that’s where those sweet, sweet grant dollars are…) and to the inescapable nature of ageing and death.
Back in 1881, the great German cell biologist August Weissman was pondering the nature of life. He figured that death must, inevitably, come to us all because old, worn-out tissues couldn’t keep on renewing themselves forever.
Then in 1965, Leonard Hayflick finally managed to show that this was sadly true. After trying to grow healthy human cells in Petri dishes in the lab, Hayflick realised that there was a finite number of times they could divide before they gave up the unequal struggle and died – it’s now known as the Hayflick limit in his honour.
That’s because most regular cells in the body switch off their telomerase, so they can no longer copy their telomeres when they divide. Over time, the telomeres get shorter and shorter, eventually fraying the ends of the chromosomes like a frayed shoelace that’s missing its aglet and triggering a crisis when the cell realises that there are all these apparently broken bits of DNA hanging around. The result is either a kind of long-term sleep known as senescence, or death.
It’s worth pointing out that the Hayflick limit has really only been tested in cells grown in the relatively harsh conditions of the lab and may not reflect the situation inside a nice cosy body. Even so, we know that there are some kinds of cells that manage to break the Hayflick limit.
One obvious example is the stem cells that are responsible for creating eggs and sperm, as it’s obviously very important that the next generation starts off with a full-length set of genetic shoelaces. Another is cancer cells, which reactivate telomerase in order to become immortal and keep on dividing unchecked forever.
Telomeres and telomerase are now a hot topic in ageing and cancer research and have also been implicated in other diseases. There’s a huge amount of interest in using the length of people’s telomeres as a measure of health, ageing and disease, not to mention enterprising scientists and biotech companies searching for the elixir of youth by trying to turn telomerase back on.
However, this has proved to be tricky, and it wasn’t until 2018 – around 30 years after Greider and Blackburn’s discovery of telomerase – that researchers finally figured out the fine details of the three-dimensional structure of the human version, which is an important step towards finding drugs that can act on it.
So while it’s looking unlikely that telomere targeting drugs will enable us to cheat death forever, I think there’s a chance that tying up nature’s shoelaces might help to keep us dancing for longer.
References and further reading
Telomeres and telomerase: three decades of progress. Jerry W. Shay & Woodring E. Wright Nature Reviews Genetics volume 20, pages299–309 (2019) https://www.nature.com/articles/s41576-019-0099-1
A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. Blackburn EH, Gall JG. J Mol Biol. 1978 Mar 25;120(1):33-53. https://www.ncbi.nlm.nih.gov/pubmed/642006
The Ends Have Arrived. Virginia A. Zakian. Cell. 2009 Dec 11; 139(6): 1038–1040. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2963196/
First detailed structure of telomerase revealed. Technology Networks https://www.technologynetworks.com/proteomics/news/first-detailed-structure-of-telomerase-revealed-300164
Telomeres and Telomerase: From Discovery to Clinical Trials. David R. Corey. Chem Biol. 2009 Dec 24; 16(12): 1219–1223. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810624/
The limited in vitro lifetime of human diploid cell strains. L Hayflick. Experimental Cell Research Volume 37, Issue 3, March 1965, Pages 614-636 https://www.sciencedirect.com/science/article/pii/0014482765902119?via%3Dihub
2009 Nobel prize in physology or medicine https://www.nobelprize.org/prizes/medicine/2009/summary/