The question of the actual mechanisms of aging has been one of the most challenging questions mankind has ever faced. Weismann himself, recognizing the signif-icance of this question, carefully considered the possible mech-anisms of the body’s aging. In 1881, he delivered a lecture to his fellow scientists at the Association of German Naturalists called “Über die Dauer des Lebens,” or “The Duration of Life.” It was the first effort to uncover the mechanisms of aging of the multicellular animal utilizing the sciences of cell biology and evolution.
“Let us now consider how it happened that the multicellular animals and plants, which arose from unicellular forms of life, came to lose this power of living forever. The answer to this question is closely bound up with the principle of division of labor... the first multicellular organism was prob-ably a cluster of similar cells, but these units soon lost their original homogeneity... the single group would come to be divided into two groups of cells, which may be called somatic and reproductive. As the complexity of the metazoan body increased, the two groups of cells became more sharply separated from each other. Very soon the somatic cells surpassed the reproductive in number, and during this increase they became more and more broken up by the division of labor into sharply separated systems of tissues. As these changes took place, the power of reproducing large parts of the organism was lost, while the power of reproducing the whole individual became concentrated in the reproductive cells alone. But, it does not therefore follow that the somatic cells were compelled to lose the power of unlimited cell reproduction.”
So, Weismann made the astonishing prediction that while the germ-line cells of multicellular animals, such as humans, were immortal (specifically, they could replicate without limit), the somatic cells were in fact mortal—that is, they had the capacity to divide only a finite number of divisions:
“Death takes place because a worn-out tissue cannot forever renew itself, and because a capacity for increase by means of cell-division is not everlasting, but finite.”
In 1961, the cell biologist Leonard Hayflick published the seminal work that convinced the scientific community that cells in the human body, the somatic cells, are mortal. They could divide and proliferate, but as Weismann had predicted so many years earlier, even with optimum growth conditions they always eventually exhausted this ability and arrested their growth.
When I entered the field of aging research in the late 1970s, Hayflick’s observation was already dogma. Humans are an amalgam of cells, some mortal and others immortal. Everyone is painfully aware of the mortal ones. Like bricks that are mortared side by side to construct the walls of buildings, so our cells are cemented together to form the tissues of our bodies. And those tissues—our bones, blood, and skin, and the cells from which they are made—are all destined to age. We are made of mortal stuff. Our body’s cells and therefore our bodies themselves share a common sentence of death. So, it may surprise you to learn that there is an exception.
Heirs of Our Immortal Legacy
Still resident in the human body are potential heirs of our immortal legacy, cells that have the potential to leave no dead ancestors, cells from a lineage called the germ-line. These cells have the ability for immortal renewal as demonstrated by the fact that babies are born young, and those babies have the potential to someday make their own babies, and so on, forever.
In 1997, we at Geron Corporation, along with a host of collaborators, finally succeeded in isolating the gene that we reasoned should impart this capacity for unlimited replication in germ-line cells. The gene encodes a protein called telomerase that rewinds the clock of aging at the ends of the chromosome. The isolation of this “immortality gene” stirred considerable controversy as to its potential to “rewind” the Hayflick clock in cells in the human body after we showed that it actually works on cells cultured in a laboratory dish. Introducing the gene in an active state literally stops cellular aging. The cells become immortal but are still otherwise normal. This procedure, sometimes referred to as telomerase therapy, may indeed one day provide a means of transferring some of the powers of immortal renewal into at least some of the cells of the body. But it has proven difficult to efficiently introduce this, or indeed any gene, into most tissues in the human body.
And so, in the meantime, my mind turned to other ways to mine the rich vein of gold of the immortal germ-line. One fall day several years earlier, I took a break from working on telomerase and walked along the San Francisco Bay waterfront. I began thinking about what are called stem cells. A stem cell is a cell that can branch like the stems of a tree, either making another stem cell or changing to become a more specialized cell. There are all kinds of stem cells in the body, some more “potent” than others (that is, some with the potential to become more cell types than another).
I wondered that day whether it would be possible to grow a human totipotent (pronounced “toe-TIP-oh-tent”) stem cell in the laboratory. A human totipotent stem cell, though entirely the-oretical at the time, could potentially branch into any cell in the body. If we imagine the branching of the fertilized egg cell into all the cells in the body, these totipotent stem cells would be analogous to the trunk of the tree of cellular life, the mother of all stem cells.
I was well aware of Weismann’s work from my years working on cellular aging, and it occurred to me that if we could isolate and culture such cells from the human germ-line, they might be naturally immortal and telomerase positive, at least until they are directed to become a specific mortal cell type. And, most important of all, all the cells that come from them would be young, just as babies are born young.