Updating Magic Universe
No, they can’t predict how long you’ll live
Excitement today in the media about the discovery of human genetic peculiarities associated with living to an exceptional old age leaves me sniffy. At the close of the story in Magic Universe called “Immortality: should we be satisfied with 100 years?” I recall:
On the day of his assassination, at what was then the ripe old age of 55, Julius Caesar declared, according to Shakespeare:
Of all the wonders that I yet have heard, / It seems to me most strange that men should fear; / Seeing that death, a necessary end, / Will come when it will come.
The veteran soldier would be bemused by 21st-Century hypochondria. In defiance of common sense and medical economics, the generation with the best life expectancy in history is obsessed with longevity.
Although overpopulation is said to be a great global problem, health educators insist that it is one’s duty to abjure motorbikes and butter and to live as long as possible. Yes, even though longevity may bring physical or mental incompetence so severe that it will cost more to keep you zimmering than to feed an entire African orphanage. As for the fear of death, if Christopher Columbus had been as bridled by cautious officials as astronauts are, his flotilla would not have quit the mouth of Spain’s Rio Tinto.
In the absence of significant disease, ageing sets a natural limit to the human lifespan. According to [Leonard] Hayflick it is about 125 years. Very few people lived past 75 until the 20th Century. But by 2000, 75 per cent of the inhabitants of the most affluent countries were doing so. The greying of the populations took actuaries and the medical profession by surprise.
The increase in human longevity slowed down in the closing decades of the 20th Century. Life expectancy at birth in affluent countries may level out at 80-90 years by the mid-21st Century. As the ageing process makes everyone more vulnerable to disease and gross degeneration, further prolongation of life may require medications yet to be invented.
They are not necessarily a good idea. Foreseeable problems range from tyrants who refuse to die to simply losing the carefree pleasures of retirement if young earners should decline to carry the economic burden of the elderly. Hayflick asked, ‘Would the least imperfect scenario be a future society in which everyone lived to their 100th birthday in good physical and mental health, then to die on the stroke of midnight?’
As Magic Universe relates earlier, Hayflick is the US microbiologist who around 1960 falsified a 30-year-old assertion by a French Nobel prizewinner that ordinary animal cells grown in a lab culture would thrive indefinitely. The natural lifespan of cells in culture, through a few dozen divisions at most, came to be called the Hayflick limit. In 1971, Alexey Olovnikov in Moscow speculated that every time a cell divides the telomeres, the DNA tie-strings at the very ends of the chromosomes, get slightly shorter, and this conjecture was fully verified 20 years later by the Canadian-born biochemist Calvin Harley and his colleagues.
Meanwhile, Thomas Kirkwood at Newcastle pointed out that burdening an animal with the genetic resources that might delay ageing is pointless if it is going to die young, because of the hazards of life. There is a trade-off between youthful vigour and provision for later life. Kirkwood called his idea the disposable soma theory, and evidence in its favour accumulated in the decades that followed.
Any update belongs before the closing section that I’ve quoted, because that still represents Hayflick’s opinion and my own.
Long life runs in families, and the genetics began to emerge in 2010. After comparing DNA from more than a thousand centenarians with a similar sample from the general population, Thomas Perls and his and colleagues at Boston University reported that they had found “genetic signatures” of exceptional longevity. These took the form of clusters of misprints in the DNA called “single-nucleotide polymorphisms” or snips, and 90% of centenarians could be grouped into one or another of 19 different clusters. Besides predicting exceptional longevity with 77% accuracy, using 150 snips, the team found variations between the clusters in the onset of age-associated diseases.
About these results from Boston, Kirkwood at Newcastle commented:
“They are not suggesting that they can screen the genes of you and me, for example, and tell us the chance we will live to 100. This would be a tall order indeed, given that only a quarter of what determines the length of human life is genetic. … From what we know already, it is rather unlikely that genetic screens will ever be able to forecast how long an individual will live.”
References for the Update
N. Calder, Magic Universe, pp. 423-428, Oxford UP 2003
Perls ref.: Paola Sebastiani et al., “Genetic Signatures of Exceptional Longevity in Humans”, Science Express, 1 July 2010.
Tom Kirkwood, The Independent (London), 2 July 2010
ADDITION 3 July. I really should take the opportunity to put in a brief but more significant update, about the role of telomerase. It also gives me a diagram for the blog, and it reassures me in my lifelong self-imposed task of reporting Nobel-prizewinning discoveries long before the prizes are handed out.
A passage in that story in Magic Universe, “Immortality: should we be satisfied with 100 years?”, reads as follows.
Steps to a denouement
A Canadian biochemist Calvin Harley latched onto Olovnikov’s theory of telomere erosion soon after it came out. He wanted to know why human beings age and in the 1980s, at McMaster University in Ontario, he grew cell cultures to investigate the question. At first Harley could see no technical means of verifying Olovnikov’s idea. These became available, step-by-step, starting with discoveries in other places and in creatures apparently very different from ourselves.
Step 1 came from research at Yale on a single-celled organism, the protozoon Tetrahymena that lives in ponds. Like yeast, it is immortal in the sense that it reproduces itself ad infinitum by cell division, and its telomeres do not erode in the manner predicted by Olovnikov. In 1978 Elizabeth Blackburn discovered that the bug’s telomeres consist of the same six letters of DNA code, repeated again and again.
Later, at UC Berkeley, Blackburn and a graduate student Carol Greider took Step 2. In 1985 they announced the discovery of telomerase as the enzyme responsible for making the telomeres. ‘We suggested that telomerase would compensate for the incomplete replication of chromosome ends,’ Greider recalled later. ‘This would explain the telomere length maintenance seen in organisms such as Tetrahymena and yeast.’
But what was the relevance of the telomeres of a pond bug to matters of human ageing and cancer? Step 3 began with a chance encounter, when Greider was on a trip to Ontario visiting a friend Bruce Futcher, who was doing research on yeast at McMaster. That was in the lab next door to Harley’s, and when she met him she found they had a common interest in telomeres. They talked hopefully about possible joint experiments.
In 1998, Greider phoned Harley with exciting news from the Cold Spring Harbor Laboratory, New York, where she and Fuchter had gone to work. Scientists there, and others working independently at Los Alamos, had found the composition of telomeres in vertebrate animals like us. Just as in Tetrahymena, they consist of a multiple repetition of six letters of DNA code. The only difference is that TTGGGG has become TTAGGG.
The time was ripe for those joint experiments on human cells, and by 1990 Harley, Fuchter and Greider had completed Step 3. They published a full experimental verification of Olovnikov’s theory, in modernized form. Ageing in human cells occurs by the loss of one TTAGGG sequence from the telomere tie-string on each chromosome, every time a cell divides.
Next, Harley and Silvia Bacchetti at McMaster established the links between activation of the telomerase enzyme, telomere maintenance and human cancer. In brief, it is the availability of telomerase that makes a cancerous cell dangerously immortal, by dodging the Hayflick limit. And Harley also proposed that the telomere-telomerase relationship was the Holy Grail long sought by scientists and medics concerned with the processes of ageing.
‘Telomere length and telomerase activity appear to be markers of the replicative history and proliferative potential of cells,’ he wrote in 1991. ‘The intriguing possibility remains that telomere loss is a genetic time bomb and hence causally involved in cell senescence and immortalization.’
The prospect of anti-ageing drugs, for medical and cosmetic purposes, attracted commercial funding. Harley joined the Geron Corporation in California. With colleagues there and at Colorado and Texas-Dallas, Harley went on to consolidate the telomere hypothesis of cellular ageing in humans. By 1997 he and his team had found the key gene that reactivates telomerase in human cells and so refreshes their telomeres. It’s called the human telomerase reverse transcriptase gene. That’s a bit of a mouthful, yet it seems uncannily like the elixir of youth about which the ancients fantasized.
It comes with a health warning. As cancer cells use telomerase to achieve their deadly immortality, stimulating the renewal of tissue cells by artificial methods might provoke tumours. Indeed the first priority for using the knowledge about telomeres was to develop inhibitors of telomerase as a means of fighting cancer. Nevertheless, at Geron and elsewhere, cautious activation of telomerase seemed to offer new prospects for treating degenerative diseases.
3 July Update
For their discovery of telomerase, Elizabeth Blackburn and Carol Greider Shared the 2009 Nobel prize for physiology or medicine with Jack Szostak of the Harvard Medical School. What Szostak did, back in 1982, was to join Blackburn showing that telomere DNA from the pond protozoon Tetrahymena, protected chromosomes in yeast – first promising that telomere DNA with its characteristic sequence should be present in most fungi, plants and animals, including humans.
Reference for the 3 July Update
Nobel press release 5 October 2009 http://nobelprize.org/nobel_prizes/medicine/laureates/2009/press.html