By Dean A. Haycock

Special to BioWorld Today

Travel along a human chromosome in either direction and eventually you come to the end of the line. You know you have reached the end when you encounter a telomere, a repeated TTAGGG sequence of the DNA alphabet.

These extensions serve as chromosome end caps. They protect and buffer the useful genetic information situated near the tips of chromosomes from wear and tear. They also make it easier for the enzyme that copies DNA in dividing cells, DNA polymerase, to perform its task as it nears the end of the molecule it is copying.

In recent years, telomeres have attracted the attention of many biologists, several biotechnology companies and investors. This is not surprising since mortality and immortality, life and death, have been linked ¿ at least on the cellular level ¿ to one feature of telomeres in particular: their length. Cancer cells, which can divide indefinitely, have been shown to maintain the length of their telomeres. Healthy cells, in contrast, inexorably experience a shortening of telomere length, stop dividing and die. Supplying cells with telomerase, the enzyme that adds to telomere DNA, however, can extend their life span in culture.

Now the telomere story itself is being extended by new research showing that telomerase can prolong the life span of human cells without lengthening telomeres. The latest installment of this tale appears in the March 30 issue of the Proceedings of the National Academy of Science in a article titled, ¿Telomerase extends the life span of virus-transformed human cells without net telomere lengthening.¿

¿The whole point of telomerase was to make telomeres longer. Now we find that it is not,¿ Elizabeth Blackburn, professor and chair in the School of Medicine, University of California, San Francisco, told BioWorld Today.

Blackburn and her colleagues studied human cells, fibroblasts, in culture. The life span of these cells was extended by expression of a viral oncogene. This genetic manipulation changed the fibroblasts into a ¿pre-cancerous¿ line of cells. The genetically engineered reprieve from death they enjoyed was only temporary. Although the cells live longer than untreated cells in culture, they are not immortal. Eventually, they experience what researchers call a ¿growth crisis¿ and fail to proliferate.

A logical explanation for their decline was, not surprisingly, shortening of their telomeres.

TERT-Treated Cells Attain Immortality

Here is where Blackburn and her co-authors step in. They introduced a human gene that encodes a protein called TERT into the cells. TERT activates telomerase. Not surprisingly, the TERT-treated cells lived on and, in fact, achieved cell culture immortality. They resumed dividing and showed fewer chromosomal abnormalities, both of which indicate that telomeres were in place and performing their protective functions.

The next observation was very surprising: The telomeres in the ¿saved¿ cells continued to shorten. This obviously is not a result one would expect in cells made immortal by a treatment that increased a substance (TERT) that stimulated an enzyme (telomerase) that lengthens telomeres. The chromosome caps in the treated cells even shortened to average lengths smaller than those found in other cells that could no longer divide. It therefore appears as if human telomerase can somehow promote survival and proliferation in cells with telomeres so short that they would, in the absence of the enzyme, stop dividing and die. How telomerase stabilizes the shortened chromosome tips is unknown.

¿There is a whole new function which is just simply to protect the ends of telomeres. That had not been shown in human cells before,¿ Blackburn said.

If telomeres are long, this protective function of the enzyme may not be so important. ¿But when telomeres get shortened to a middle¿ size, then it becomes more important to have telomerase around,¿ Blackburn added.

Thus the authors suggest that the stabilizing role of telomerase is needed only when telomeres are shortened to some critical threshold.

New Insights Have Therapeutic Implications

The new insights into telomere biology have many implications for those interested in exploiting telomerase for therapeutic and basic research purposes. In the past, for example, some researchers have tried to use telomere length to monitor cell division in populations of cells, according to the author. ¿Now you absolutely have to know if telomerase is on¿ or off¿ in these cells. If you want to use telomere length as a diagnostic in some way, you also have to know if telomerase is active,¿ Blackburn said.

The results also raise the possibility of protecting cells that have shorter telomeres than desired. Blackburn offers an example. ¿If you were putting bone marrow cells in [to a patient], you might want those cells to be fixed up right away. All you have to do is get telomerase in. It doesn¿t have to spend time building those telomeres up to get them stable again. They can be stabilized without lengthening. That is the good news part,¿ Blackburn said.

There is, of course, a ¿bad news¿ part of the finding. ¿It has been long suspected that telomerase must be helping cancer cells become or stay cancerous because so many cancers have telomerase. But it wasn¿t quite clear how it was doing it. Pre-cancerous cells normally commit suicide but telomerase lets them get past that.¿

To Blackburn, that is a red flag. ¿If there is a cell on its way to becoming cancerous and you put telomerase in, you may increase the chances of it becoming cancerous. I think telomerase is good news when the cells are normal, when they don¿t have any pre-cancerous signs.¿

In a commentary in the same issue of PNAS, Arthur Lustig of Tulane University Medical Center in New Orleans concluded, ¿However, the rationale for the medical use of telomerase drugs depends on a strong and direct connection between telomerase activity in vivo and oncogenesis. What is truly necessary now is a manipulatable genetic system for analyzing the provocative proposals based on in vitro studies in an in vivo setting. More answers to these questions are undoubtedly around the corner.¿

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