Back to Immortality

How Scientists Propose to Rejuvenate Aging Humans enlarge image

On a warm, still summer night in August 1999, I stood in an Indiana hospital intensive care unit and turned my head to look at the clock. It was nearly 2 a.m., the dark and deep hours before the morning light, when most human deaths occur. My dear mother’s heart raced at 140 beats per minute, but that was about to end. She was dying, the woman who had given me life. I had long devised a plan that I hoped would one day help her, a plan some 20 years in the making. It was a plan to profoundly intervene in the biology of human aging. But I must say, my best efforts seemed impotent at that moment, staring into the icy face of death.

At my request, a nurse pinched her fingernail bed one more time with a hemostat, squeezing her tender fingertip with the force of a pair of pliers. She winced, though imperceptibly. That was enough for the attending physician. She ordered the respirator that periodically forced air into my mother’s lungs to be turned off along with the intravenous dopamine that was driving her heart. My eyes were fixed on the monitors. Mom’s chest flattened. Her heart at first maintained its steady rhythm of 140 beats per minute and then slowly began its descent, drifting downward like a falling leaf in autumn—140, 125, 110, 100…

My mind flashed back to a fall day in 1960 when I was seven years old. My mother and I walked along the sidewalk, on our way to the corner store. Suddenly, from above, a red leaf began a slow descent from the top of a tree in front of us. The leaf fell among some bushes alongside the sidewalk and I stopped to pick it up. “Mom, look, a cocoon.” There among the fallen leaves was a gray cocoon, as big as your thumb, woven between the stems of a branch. I snapped it off and on we went to the store.

When we got home, my mother propped the cocoon on a ledge near a frosted kitchen window and I forgot about it over the long Michigan winter months. Then one spring day, a miracle happened. My mother and I had just stepped out of the car and my sister came running, screaming, “Hurry, you gotta see!” Running into the kitchen I stopped at the door in amazement. A spectacular moth sat perched on the windowsill, more colorful, larger, more wonderful than anything I knew existed—six inches from wing to wing, and painted in deep velvety colors of the rainbow. The miracle of this immortal cycle of metamorphosis—egg, caterpillar, moth and back to egg again—never left this young boy’s mind.

The Cycle of Life
For millennia our ancestors were observant enough to recognize the profundity of the cycle of life, and the fact that there is a sense in which life is immortal. While it is true that the individual plant ages and dies, out of the sun-drenched soil of spring a resurrection of plant life occurs every year. And while the individual zebra dies, as far back as anyone can remember there have always been zebras, and they always wear stripes. In other words, there is an immortal substratum of life, a continuum that connects the generations – a cycle of life, an immortal cycle. The individual passes away, but there is a continuity of individuals. The ancients attributed the force of this continual renewal of life to the realm of the gods.

The ancient Egyptians witnessed this immortal cycle of renewal on the banks of the river Nile. They came to revere its permanence. Like the sun that dies every evening in the western sky, only to be reborn the following morning, so the life of the individual is a transient phenomenon, but the immortal cycle of life itself is unchanging. In the mind of the ancient Egyptian mythologist, the phenomenon of immortal renewal was more than just a scientific observation; it was the cornerstone of the meaning of life itself. It was (so they reasoned) the work of a god, and they called that god Osiris.

Osiris, often depicted with his face painted green to symbolize this force of immortal renewal, was the foundation of ancient Egyptian religion. Osiris not only escaped death and corruption himself, but, inasmuch as any of his disciples could learn the mystery of the path into immortality, he too could hope for an immortal renewal of life transcending death.

Immortal Cells
I think the ancient Egyptian philosopher would have marveled to know that from the dry desert sand, future scientists would learn to make clear glass, and then to mold that glass into lenses, and then to stack those lenses together to make telescopes to magnify the night sky, and microscopes to magnify the world too small for the unaided eye. The microscope allowed early biologists to peer into the cellular substructure of life, and by the mid-1800s, it was confidently asserted that the mechanism of animal reproduction was via cells, not some amorphous “life force.” All life comes from pre-existing life, and all cells come from pre-existing cells. In other words, science had uncovered the force of immortal renewal. It was an invisible thread that connected the generations, a lineage of microscopic primordial cells.

The German scientist August Weismann clearly understood the implications of this observation. The cell theory implied that life on our planet today likely originated many millions of years ago from single-celled animals that were immortal. By immortal Weismann did not mean to imply that they could not be killed. Indeed, the struggle of the fittest implied that their less-fit cousins did indeed die. By immortal Weismann meant only that they need not die—that given proper nutrition, and barring some accident, any particular cell could continue dividing, leaving no dead ancestors in its wake.

Weismann then suggested that these original immortal cells may have clung to their daughter cells after dividing, thereby forming a small cluster of identical cells. It is then easy to imagine that these cells simply surrounded themselves with daughter cells to aid in their competition for immortality. One could imagine, for instance, that by “holding hands” in this manner, they were better able to move through the water, or perhaps better able to avoid being eaten by some other animal.

Specialization of Cells
But complex, multicellular animals like you and me do leave dead ancestors behind. When and why did that happen? Here is where Weismann made a revolu-tionary proposal. He surmised that some of the cells in this cluster changed in a profound manner. When the largest animal was still a small cluster of cells—perhaps something like the ball of cells called Volvox, the microscopic pond water animal—some of these primordial and immortal cells specialized in a subtle way to facilitate the reproduction of their sister cells. These specialized cells, which are called somatic cells (from the Greek word soma, meaning body), lost the ability to create other organisms like themselves. They had irreversibly specialized.

For the first time in history, a specialization of cell types arose. The change may have made the entire organism more fit compared to its competition, but the cost was that the somatic cells were destined to die, losing the potential for their own immortality. This, Weismann argued, was the first time programmed death appeared. As Joseph Wood Krutch (1856) put it:

“The amoeba and the paramecium are potentially immortal... But for Volvox, death seems to be as inevitable as it is in a mouse or in a man. Volvox must die as Leeuwenhoek was to die because it had children and is no longer needed. When its time comes it drops quietly to the bottom and joins its ancestors. As Hegner, the Johns Hopkins zoologist, once wrote, ‘This is the first advent of inevitable natural death in the animal kingdom and all for the sake of sex.’”

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.”

Hayflick’s Experiment
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.

Stem Cells
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.

Embryonic Stem Cells
In the following years and through the hard work of collaborators such as Jamie Thomson of the University of Wisconsin at Madison and John Gearhart at Johns Hopkins School of Medicine, the cells were finally isolated. Called human embryonic stem cells because they come from human pre-implantation embryos (microscopic balls of cells that have not yet begun to develop and attach to the uterus to begin pregnancies), these cells have fulfilled their promise in displaying the awesome power of making any cell type in the human body. And as we hoped, they made young cells that could theoretically be used to repair or replace aged or diseased cells and tissues.

President George W. Bush addressed the American people on August 9, 2001, to describe his policy relating to human embryonic stem cell research. He suggested that all federal funding be limited to the number of cell lines that had been isolated as of that date. He expressed his moral concerns about further efforts to isolate the cells, stating his religious belief that the entities from which the cells were derived were not in fact simply a clump of unformed cells, but instead were in fact very small people.

There are several problems with the President’s position. The practical one is that even if federal funding led to our ability to efficiently manufacture some cells of great therapeutic value, they would not be available to you—that is, the body would in most cases reject the transplanted cells as being a foreign invader. The miracle in the laboratory could not easily lead to a comparable miracle in the hospital bed.

Therapeutic Cloning
And so in 1999, my colleagues and I proposed a controversial solution. We argued that the procedure called nuclear trans-fer—the transfer of a somatic cell into an enucleated egg cell—not only could produce embryos that when transferred into a uterus could produce a clone, but could also be harnessed to make embryonic stem cells as well. Such cells would be essentially identical to the patient’s cells. This could potentially solve the remaining problem of histocompatibility by creating human embryonic stem cells and then any cell in the body, all of which should never be rejected by the patient.

The use of somatic cell nuclear transfer for the purposes of reversing time’s arrow on a patient’s cells has been designated therapeutic cloning. This terminology is used to differentiate this clinical indication from the use of nuclear transfer for the cloning of a child, which in turn is often designated reproductive cloning.

Since the debate over thera-peutic cloning began, the power of the technique has become increasingly impressive. In April 2000, my colleagues and I reported evidence that the egg cell could act as a “cellular time machine,” not only reversing the arrow on differentiation (that is, not only converting a body cell like a skin cell into an embryonic stem cell), but also doing the unimaginable, returning the aged body cell to immortality and rewinding the clock of cellular aging as well. These results, now reported for multiple mammalian species, suggest that we may have the potential to reverse the aging of human cells in the same manner.

This would mean that we could make young cells of any kind for a patient of any age. While this “time machine” is expected only to be big enough to take on a single cell, the resulting regenerated cells could theoretically be expanded and turned into cells that repopulate our blood with young immune cells, or cells that can re-seed our blood vessels with fresh young cells, or indeed young cells of any kind to treat a vast array of currently untreatable diseases.

Heated Controversy
Despite the good intentions of researchers in this emerging field of regenerative medicine, these technologies have been at the center of one of the most heated controversies in the history of science. The raging controversy over embryonic stem cells and cloning has deeply divided our nation, and the stem cells’ profound implications for battling the manifestations of age-related degenerative disease have raised concerns that mankind may be meddling in technologies that will anger the gods themselves.

In the face of lives molded and bounded by death, we are forced to choose our own position on these new technologies. In the summer of 1999, as I stood with my mother in a small hospital room, I knew my position in the debate. I would do anything to save the life of my mother—anything, that is, short of harming an actual human being.

And I had strong reasons to believe that therapeutic cloning would not have to create an individualized human being, even at the earliest states of development. I would risk my life, my finances, my reputation; I would give anything to help her.

Dr. Michael D. West (pictured above) is CEO of Advanced Cell Technology. In 1990 he founded Geron, the first prominent biotech-nology company to focus on human aging, where he served as a director and vice president until 1998.

Death Is the Enemy
My mother’s pulse continued its downward glide—90, 80, 20, 10, 8… I thought to myself, her heart was solid, I would never have worried that she would have died of heart failure. I saw in my mind the swelling imbalance in blood chemistry, the millions of cells in her body screaming for help, her precious mind being turned to chaos by anoxia. Finally her heart cells—facing, for the first time since the origin of life on earth, the abyss of death—gave up their valiant defense of life and fell into chaos and arrhythmia. They had accomplished their appointed goal; they had successfully passed on their genome into a son. Minutes passed. As successful as my mother’s life might have been in completing the job of reproduction, I found the strategy of the life cycle completely unacceptable. I stood there, hating death.

I walked to my car later that night, wandering aimlessly into the darkness. I had no itinerary, no plane reservations; I felt like driving randomly into the night. I looked overhead in that warm summer sky and stared at a bright but waning moon and I recognized its significance. The moon has for millennia been a source of encouragement to mankind facing the bleak realities of death and of loss. In 14 days, it is cut into pieces like the death of Osiris, but it always regenerates in an eternal fugue.

In the years to come, science and medicine will deliver on the promise of regenerative medicine. It is inevitable that the immortal cell, which can do so much to alleviate human suffering, will find its way to the hospital bed. But when these new therapies are available for our loved ones entirely depends on how we as a society grapple with these important issues.

The United States has a proud history of leading the world in boldly exploring new tech-nologies. We did not hesitate to apply our best minds in an effort to enable a man to walk on the moon. We were not paralyzed by the fear that we would anger the gods by reaching for the heavens. But a far greater challenge stands before us now. We have been given two talents of gold. The first, the root of immortal human life, is the human embryonic stem cell. The second is nuclear transfer technology. Shall we, like the good steward of the Bible, take these gifts to mankind and courageously use them to the best of our abilities to alleviate the suffering of our fellow human beings, or will we fail most miserably and bury these gifts in the earth?

I am confident that the United States, which historically has led the way in advancing technology, will find the courage to lead in regenerative medicine as well. I only hope we will do so quickly; time is not on our side.