Over a century ago, a scientist in a New York laboratory peered at the cells he had cultivated in flasks and wondered whether he might have uncovered the secret of immortality.
Alexis Carrel was a French surgeon who by then was already famous for having pioneered techniques to reconnect blood vessels that had been severed in an accident or an act of violence such as a stabbing. His method for joining blood vessels end to end with tiny, almost invisible sutures transformed many kinds of surgery, and is the basis of organ transplants even today. In 1904 Carrel left France for Montreal and then Chicago. Two years later, he moved to New York City to become one of the earliest investigators at the newly created Rockefeller Institute for Medical Research (now Rockefeller University). The institute offered an unparalleled environment for an ambitious scientist, including superb laboratories and sizable endowments. And the thirty-three-year-old Carrel certainly had ambitions.
As a surgeon, Carrel dreamed of keeping tissues alive outside the human body. In the lab, we can grow cultures of bacteria or yeast indefinitely. Although individual bacteria or yeast can age and die, the culture continues to grow and is, in a sense, immortal. But that was not clear for cells and tissues from higher life forms such as us. At Rockefeller, Carrel began a long series of experiments to see whether a culture of cells from a tissue could be kept alive indefinitely. By placing the cells from the heart of a chicken embryo in a special flask, and steadily supplying them with nutrients, Carrel seemed to have made a breakthrough. The culture could be maintained for years. These cells, he claimed, were immortal.
The discovery was reported with great fanfare. If cells from a tissue could be made immortal, journalists reasoned, then so could entire tissues and eventually us. An editorial in the July 1921 issue of Scientific American gushed, “Perhaps the day is not far away when most of us may reasonably anticipate a hundred years of life. And if a hundred, why not a thousand?”
But Carrel was wrong.
Initially, his work went unchallenged because of his stature, and, over the years, the immortality of cultured cells became dogma. That is, until three decades later, when a young scientist at the Wistar Institute in Philadelphia, Leonard Hayflick, wanted to see if cells would change when exposed to extracts from cancer cells. He decided to use Carrel’s method to grow human embryonic cells in culture. To his disappointment, he found he could not grow these cells indefinitely. Initially, Hayflick, a recent PhD in medical microbiology and chemistry, thought he must have made a mistake. Perhaps he hadn’t correctly prepared the nutrient broth or was washing his glassware improperly. But over the next three years, he carefully ruled out any technical problems and concluded that the prevailing theory was simply incorrect: normal human cells would not replicate indefinitely in culture. They were not immortal.
Instead, Hayflick found that his cells would divide a finite number of times and then stop. In an ingenious experiment, he and his colleague Paul Moorhead took male cells that had already divided many times and mixed them with female cells that had divided only a few times. When they soon reached their limit, the male cells stopped dividing, while the female ones continued to grow to the point that they came to dominate the culture. Somehow the old cells remembered they were old, even when surrounded by young cells. They were not rejuvenated by the presence of the young cells, nor did they stop dividing because of some contaminating chemicals or viruses in the environment. Hayflick and Moorhead coined the term senescence to describe this state, in which the cells were arrested and could no longer divide further.
Another junior scientist might have been nervous about challenging such established ideas, but not the confident Hayflick. He and Moorhead wrote up their results in a meticulously detailed thirty-seven-page paper and submitted it to the same journal in which Carrel had published his original findings. Because it went counter to the prevailing dogma, and perhaps because the editor was a colleague of Carrel’s and more inclined to trust him than some young unknown scientist, the paper was rejected but eventually published in Experimental Cell Research in 1961. It has since become a classic in the field. The number of times a particular kind of cell can divide is now called the Hayflick limit.
How did Carrel get it so wrong? One possibility, suggested by Hayflick himself, is that the French scientist may have inadvertently introduced fresh cells into the culture each time he replenished the nutrient broth in which they were growing. Some have even suggested that fresh cells may have been incorporated deliberately, although this would be a case of either egregious misconduct or sabotage.
My sneaking suspicion is that by the time Carrel worked on these cells, fame and power had gone to his head, and he had become arrogant and less self-critical about his research. This attitude manifested itself in other ways. In 1935 he published a book titled Man, the Unknown, which recommended sterilizing the unfit and gas chambers for criminals and the insane, and commented about the superiority of Nordic people over southern Europeans. In the preface to the book’s 1936 German edition, he praised the Nazi government of Adolf Hitler for its new eugenics program. Given Carrel’s stature, it is quite possible that the Nazis used his remarks as one justification for their activities. His plaque in Rockefeller University was recently corrected to reflect his views.
Titia de Lange, a renowned biologist currently at the very same Rockefeller University, suggested a more straightforward explanation for Carrel’s results: the laboratory next door to Carrel’s was working with malignant tumors in domestic chickens, and these cancerous chicken cells might have contaminated Carrel’s cultures growing nearby. Cancer cells are the exception to the Hayflick limit: they don’t stop dividing after a certain number of divisions, and this uncontrolled growth is why cancer wreaks such havoc on the body.
Why don’t cancer cells stop growing unlike the normal ones studied by Hayflick? And how can a cell keep count of the number of times it has divided and know when to stop?
When a cell divides, each of the DNA molecules in our chromosomes has to be copied. Unlike bacteria, whose genome consists of a circular piece of DNA, the DNA in each of our forty-six chromosomes is linear. Like an arrow, each strand of the double-helical DNA molecule has a direction, and the two strands of the DNA molecule run in opposite directions. The complex machinery that copies each DNA molecule uses each strand as a guide to make the opposite or complementary strand, but it can do so only in one direction. In the early 1970s James Watson of DNA fame and a Russian molecular biologist named Alexey Olovnikov both noticed at about the same time that the way the cell’s machinery copies DNA would create a problem at the very ends of the molecule.
One day, Olovnikov was obsessing over this idea while standing on the platform of a train station in Moscow. He imagined the train in front of him as the DNA polymerase enzyme that copies DNA, and the railway tracks as the DNA to be copied. He realized that the train would be able to copy the rail track ahead of it, but not the part that lay immediately under it. And because the train could go in only one direction, even if it started at the very end of the track, there would always be a section underneath the train that could not be copied. This failure to copy the very end of a DNA strand meant that each newly made strand would be just a little shorter than the original. With each cell division, the chromosomes would progressively shorten, until eventually they lost essential genes and could no longer divide, thereby reaching their Hayflick limit. The end replication problem, as this is known, could explain at least in principle why cells stopped dividing, although the real answer, as we will see, is more complex.
This excerpt from Why We Die: The New Science of Ageing and the Quest for Immortality by Venki Ramakrishnan has been published with permission from Hachette India/Hodder & Stoughton.