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  • The New York Times
    Immortality Beckons To Biologists

    Immortality, Of a Sort, Beckons To Biologists





    Immortality, Of a Sort, Beckons To Biologists


    Published: November 17, 1998

    In the Greek myths, a terrible price is always paid by humans who seek to live forever, as if to discourage people from even the thought of sharing in the defining attribute of gods. Tithonus, a youth with whom Aurora, the goddess of the dawn, fell in love, was granted immortality, but as he grew more bent and decrepit longed only for one other gift, the relief of death.

    Chastened by such cautionary tales, we meekly accept that death is as inevitable as the dawn, knowing that our bodies will run down like an aging automobile when they exceed their design limit. So it was almost disquieting rather than uplifting to hear scientists at the Geron Corporation in Menlo Park, Calif., talk about ''immortalizing'' certain cells that they hoped to derive from the recently isolated human embryonic stem cells. Surely the scientists were speaking metaphorically.

    They were not.

    The study of aging is undergoing a possibly profound change, and a handful of biologists, whose hubris has not yet been punished with a thunderbolt from Mount Olympus, are beginning to think about interfering with the mechanisms that make the body mortal.

    Immortalizing a cell is of course very different from making an individual live forever. But because people are made of cells the two concepts have a deep and maybe exploitable link.

    For decades biologists have known that the body's mortality is mirrored on the cellular level by an immutable rule called the Hayflick limit. Dr. Leonard Hayflick, now of the University of California, San Francisco, discovered that when tissue cells are taken from the body and cultured in a laboratory dish, they grow and divide about 50 times -- the number varies with the kind of tissue -- and then lapse into senescence.

    In January, Geron's biologists announced an electrifying finding: they had learned how to make human cells break the Hayflick limit. The physical basis of the Hayflick rule is a section of DNA known as the telomere, which gets shorter each time the cell divides. When the telomeres reach a certain minimum length, the cell is thrown into a terminal crisis.

    All cells possess a gene, known as the telomerase gene, which can restore the telomeres to their youthful length. But in most cells the gene is permanently repressed and inactive. Geron's discovery was that by inserting a copy of the telomerase gene in active form into cells, it could make them grow and divide indefinitely.

    For cells, the ability to divide indefinitely into two identical daughter cells is immortality. (The cell's atoms and molecules are continually being replaced, but its structure and informational content are unchanged from day to day.) For an individual, making clones of oneself in perpetuity would hardly count as living forever. What stands between a person and immortality is that almost all the body's cells are mortal and, though they turn over, eventually cease to replace themselves efficiently.

    Two categories of body cell, however, are immortal in the cell's sense of being able to divide indefinitely. One is the essence of life, the other of death. Cancer cells eventually learn how to unlock the bolted down switches on the telomerase gene, and with this last defense in their hands can defy all the body's careful control mechanisms and run rampant.

    The other kind of immortal cell is the all-purpose, embryonic stem cells from which the whole organism develops. In embryonic stem cells, too, the telomerase gene is active, and the cells can divide indefinitely as long as they remain embryonic. As the fetus develops, however, the embryonic stem cells differentiate, meaning that they progress down a variety of different pathways to become the specialized cells that form each of the body's different tissues.

    In the biologist's view it is differentiation, not expulsion from Eden, that makes us mortal. As cells differentiate, they repress the telomerase gene. Some, like most brain and heart cells, seem never to divide again once the organism has reached maturity. Others, like skin and blood cells, can regenerate from stem cells specific to their tissue, but these tissue stem cells, descendants of the embryonic stem cells, also have a finite lifetime.

    How then are embryonic cells generated from parents whose cells are irreversibly differentiated? In the embryo, a small number of stem cells are set aside, before embryonic development begins, and protected from differentiation. These special cells, known as embryonic germ cells, migrate to the developing ovary or testis, where they generate the egg or sperm for the next generation.

    Thus there is a special lineage of cells that permanently resist terminal differentiation, cycling indefinitely from embryonic stem cell to embryonic germ cell, to oocyte or sperm, to fertilized egg and embryonic stem cell again. At each cycle the cells spin off a new body as the temporary vehicle to carry them forward on their unending journey.

    Geron's second amazing advance of the year was the isolation of human embryonic stem cells by two groups of researchers whom the company financed. One reason for its success was that under its visionary founder, Dr. Michael D. West, the company worked with leading academic scientists in the telomere field. Because the embryonic stem cells were known to maintain permanently youthful telomeres, the company was drawn into the stem cell field and repeated the coup of signing up many of the leading university scientists in the field.

    With its human embryonic stem cells and its telomerase gene, Geron has acquired two scientifically fascinating properties, though of course commercial payoff may be years away. What the company hopes to do is to guide the embryonic stem cells down specific paths of differentiation toward becoming the specialized cells of heart, blood or any other desired tissue.

    Before being injected into a patient, these specialized cells could be immortalized by adding the telomerase gene in active form. The tissues they formed in a patient would then be permanently youthful. (There would of course be a problem of immune rejection, which Geron has not yet addressed. Dr. West, now at another company, said last week that he hoped to sidestep rejection by generating embryonic stem cells from the patient's own body cells; their differentiated state would be reversed by fusing the cell with a cow's egg.)

    If biologists can immortalize some of the body's cells by the Geron method, could they in time learn how to immortalize them all? Dr. William A. Haseltine, chairman of Human Genome Sciences in Rockville, Md., believes a solution lies with the tissue stem cells that provide for the regeneration of tissue like blood and skin. Tissue stem cells, descendants of the embryonic stem cells, may exist for many or all tissues but only a few have so far been identified.

    These tissue stem cells also get old in time and start to generate tired or compromised cells. Dr. Haseltine's idea is to replace them, before they start to do harm, with tissue stem cells immortalized with telomerase. All the body's tissues would thus be continuously and reliably regenerated from permanently youthful tissue stem cells.

    ''This is a clearly articulated vision of human immortality that will be introduced slowly over the next 50 years,'' Dr. Haseltine said.

    Dr. Thomas Okarma, Geron's vice president for research, commented sternly that his own company had no such plans.

    Making the body immortal ''is indeed fanciful and certainly something we don't even contemplate here,'' he said. ''We are much more interested in dealing with the 20 or so degenerative diseases that have no present treatment and could be addressed with immortalized cells.''

    The embryonic stem cells, immortal seeds in our mortal bodies, have a pedigree that stretches back more than 3 billion years to the first cell. Their survival mechanisms are sophisticated. Even the telomerase system is far from understood. Still, the cell is a mechanism and, absent the gods' fury, it can one day be made to operate closer to our desire than evolution's uncaring design.




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