US scientists extend the life of human cells
BMJ 1998; 316 doi: https://doi.org/10.1136/bmj.316.7127.247 (Published 24 January 1998) Cite this as: BMJ 1998;316:247
Scientists in the United States have significantly extended the life span of cultured human cells, with no sign of abnormalities, by adding an enzyme called telomerase. The work has sparked widespread excitement, leading some to believe that many age related ailments can be curtailed and that the human life span could be extended beyond 120 years.
The groundbreaking research was a collaborative effort between investigators at the University of Texas Southwestern Medical School in Dallas and scientists at Geron, a biotechnology firm in California (Science 1998;279:334-5, 339-52). They studied the cellular aging of human fibroblasts, retinal epithelial cells, and vascular endothelial cells.
Normal human cells undergo a finite number of cell divisions before entering a non-replicative state known as senescence, which is followed by cell death. The number of divisions varies between 40 and 90, depending on cell type, and is known as the Hayflick number, after Leonard Hayflick, who discovered this phenomenon in 1965. On occasion, cells can escape this fate and continue to replicate. Human germline cells retain their ability to divide, but other cells that continue to divide are often cancerous.
Previously, it had been proposed that telomeric DNA served as the molecular marker for senescence. Telomeres are highly conserved sequences of DNA that are present at the ends of chromosomes and consist of repeats of the nucleotide sequence TTAGGG. Telomeres form a protective cap around genomic DNA, preventing chromosomal loss and aberrant fusion during mitotic cycles. However, as cells age, there is a progressive shortening of telomeric DNA, and when telomeric DNA is entirely sloughed off, chromosomal degradation ensues and cells die. Support for the telomeric theory of aging is seen in the disease progeria, a rare disorder of accelerated aging. Children with this disease die in early to middle childhood with bodies of 90 year olds. Their telomeres are drastically shortened when compared to those of age matched cohorts.
This progressive erosion of telomeric DNA had long been proposed as the molecular mechanism of cell aging, but until now, direct evidence has been elusive. The researchers resolved the controversy by introducing telomerase, the enzyme which elongates and rebuilds telomeres, into cells which normally lack it. Telomerase is normally found in germline cells such as sperm and ova, as well as in several cancers, but is absent in normal somatic cells. Foreskin fibroblasts and retinal epithelial cells were transfected with the gene for telomerase and were able to use it to prevent telomere shortening and cell death. Whereas control cell lines underwent their normal number of divisions and then stopped and died, cells expressing telomerase continued to divide.
Dr Jerry Shay from the Southwestern Medical Center speculated that the cells have been immortalised: “Normally cells stop dividing after about the 70th generation. These cells are now up over 100 population doublings, and they show no evidence that they will slow down.” So far, the converted cells appear entirely healthy. Dr Shay denied that a fountain of youth is at hand but said that the finding will allow us to live a healthier, but not necessarily longer, life.
Dr Woodwring Wright, also from Southwestern Medical Center, is optimistic about the implications of the work. “This research raises the possibility that we could take a patient's own cells, rejuvenate them, then modify the cells as needed and give them back to the patient to treat a variety of genetic and other diseases,” he said, adding that it will transform genetic engineering. At the very least, researchers will be able to use the technique to prolong the life of cell cultures, so that genetic, pharmaceutical, and vaccine studies will be enhanced by the discovery.
Scientists speculate that the work will have applications in reversing macular degeneration, a common cause of blindness, in which central retinal cells die. The findings may also allow doctors to accelerate wound healing, extend the viability of bone marrow transplants, grow skin for burn victims, and combat some forms of arteriosclerosis.
Normal human cells undergo a finite number of divisions CNRI/SPL
But the flip side of the discovery is the possibility that telomerase positive cells will be more prone to cancer. Several human cancers, including prostate, breast, and ovarian malignancies, express telomerase and thus evade cell death. Telomerase expression may be a necessary step in some forms of carcinogenesis, and cellular senescence may be a method of preventing cancer. The longer a cell lives, the greater chance it has of accumulating mutations. Having a protective telomere cap may conserve deleterious and cancer causing mutations.
In an accompanying editorial in Science, Dr Titia de Lange of the Rockefeller University in New York said that the implications of the discovery are profound, especially for cancer research: “The new data indicate that activation of telomerase in human tumors bypasses cellular senescence and is thus a requirement for tumor progression … the molecular basis for telomerase deregulation in tumors should be of immediate interest … the results should strengthen the determination of those who are searching for telomerase inhibitors as potential anticancer agents.”