Telomerase
Related Terms
Aging, antibodies, antigen, cancer, cDNA, chromosomes, cytogenetics, DNA, genes, genome, molecular genetics, nucleotide, RNA, telomerase, telomeres, vaccination, vaccine.
Background
Genes provide the blueprints for growing and maintaining a living organism. Their function is to instruct cells to make new molecules (usually proteins). Proteins do all the construction in the body, make up a good portion of what is built, and perform most of the operations that make up life activities. Genes are sequences of smaller chemicals arrayed linearly on large molecules called DNA (deoxyribonucleic acid). DNA is a very long and complex chemical in the nucleus of the cell. Collections of DNA large enough to be seen under a light microscope are called chromosomes. Humans have 46 chromosomes, including 22 pairs of autosomes and one pair of sex chromosomes.
All living organisms grow one cell division at a time. Each time a cell divides into two exact copies, the nucleus with its chromosomes must duplicate itself. During this copying process each chromosome splits into two halves, and each half reproduces the other half. At the ends of each chromosome are structures called telomeres that protect the ends of the chromosome during this copying process. Telomeres do not provide instructions for making proteins but rather are involved in the mechanics of chromosome duplication. There is a problem with this process. The structure of chromosomes and the mechanics of their duplication are such that the telomeres are not completely copied during cell division. Each cycle results in a shortening of the telomeres. As a result, most cells are limited to 50 to 70 division cycles. After that number of cycles, the telomere is too short to permit chromosome copying. For this reason, the cells age and die. This appears to be a protective mechanism to prevent cells form accumulating enough copying errors to harm their host organism. Because cancer cells have unregulated growth, they escape this preventive measure. However, it is possible that there would be far more cancers and other diseases of aging if not for this process.
Some cells are considered immortal, which is to say that they are able to maintain the length of their telomeres with each cell division and can continue dividing forever. This is because they contain an enzyme called telomerase that adds length to the telomere with each cell cycle. Stem cells and 90% of cancer cells have telomerase.
The presence of telomerase in cancer cells and stem cells has two pertinent questions: 1) If all cells had telomerase would they (and all organisms) be immortal? 2) If cancer cells could be deprived of their telomerase, would they die off? There is an obvious conflict between these two questions. How can the lifespan of cells be prolonged without promoting a cancer or other diseases caused by cumulative genetic defects? One would have to disable telomerase activity in unwanted cells while promoting it in desirable (normal) cells. These questions are the object of intensive research at the present time.
Methods
Studying telomeres: The evolution of telomeres during the lifetime of an organism is studied in cell cultures in the laboratory. Cell culture is a laboratory technique that extracts living cells from an organism and places them in a laboratory environment, such as a Petri dish, where they can continue to grow. Cultures of cancer cells, for example, allow researchers to experiment with ways to kill the cancer without harming an individual who has cancer. After each cell division, a few cells are removed from the culture to determine the length of their telomeres. This is done by attaching a probe or marker to the telomere, separating it from the rest of the chromosome, and then measuring its length.
Identifying telomeres: Knowledge of the exact chemical structure of a telomere (or a gene or another segment of DNA) permits the creation of a probe or marker that attaches specifically to that segment of DNA. There are several methods for accomplishing this. For example, ribonucleic acids (RNA) can be reverse engineered to create the DNA it came from by using an enzyme called reverse transcriptase. That DNA is then converted to complementary DNA (cDNA) that will match the original DNA, nucleotide by nucleotide. A marker chemical is then attached to the cDNA. Because the marker includes a way to "see" it, researchers can find specific genes, isolate them, and work with them. Probes or markers can be seen by labeling them either with a radioactive atom or a chemical particle that glows under ultraviolet light. Fluorescence in situ hybridization (FISH) is the name of one such technique. This process identifies genetic molecules that are found in only limited situations such as infections or specific cancers and enables an exact diagnosis.
Human Genome Project: Knowledge of telomeres is one of the many gains resulting from the Human Genome Project and similar efforts to map chromosomes from many different species. The human genome project was an expensive, exhaustive work that occupied many years. The result was the identification of the complete chemical structure of human DNA. The technology used for human genes has also been used for many other kinds of creatures. There is now a vast library of genes from many different creatures that scientists can access.
Research
Basic research: The arrival of ever more efficient techniques of characterizing DNA such as polymerase chain reactions (PCR), microarray assays, and ligand-based reactions has accelerated progress in understanding telomeres, telomerase, and the role each plays in health and disease. PCR and ligand-based reactions are methods of amplifying a tiny sample of DNA, RNA, or a protein to the size where it can be studied. Microarray is a method of identifying individual molecules in a mixture of many different types using fluorescent tags.
Aging and cancer: Aging and cancer are the two areas of interest related to telomeres and are in direct conflict. Increasing telomerase activity will increase the lifespan of cells and consequently slow the aging process. However, this same increased lifespan will increase the chance of those cells becoming cancerous because cancers are due to various mutations that require multiple cell cycles to accumulate. In addition, the risk of promoting existing cancers increases because they depend upon an increased lifespan. On the other hand, decreasing telomerase activity will hinder and possibly even arrest cancer growth but will do nothing to arrest aging and may even promote it. Stem cells are essential to human life because they replace aging, worn out, and discarded normal cells throughout the body. Blood and skin are examples of tissues whose cells need to be constantly replaced.
The dilemma requires that all attempts to treat cancer with telomerase inhibitors specifically target only cancer telomerases. Current information suggests that there is enough of a difference between the telomeres in cancer cells and the telomeres in normal cells to permit treatment in humans with several versions of telomerase vaccines. Vaccines can be very specific if the antigen used in the process of vaccination to produce the antibodies can be designed to be exclusive. In a similar manner and with greater control, molecular biology techniques can exactly differentiate between stem cell telomerases and cancer telomerases and isolate one from the other using special identification and tagging techniques.
Cancer: Researchers have been studying mice engrafted with human cancers for much longer and are developing other anti-telomere agents that may soon be tried in humans. Engraftment is the process of implanting tissue from one species into another in such a way that the foreign tissue continues to grow. Transplanting human organs, such as kidneys, uses the same technology. In the case of mice and human cancers, the mouse is rendered unable to reject the transplanted tissue by altering its immune system. In this way, human cancers can be studied in living organisms without risk to humans.
Aging: No effective treatment for aging has yet been developed due to the inherent risk of promoting cancer growth. All research is directed toward further understanding of telomeres with the hope that someday a safe and effective approach will appear that does not encourage cancer growth.
Implications
General: Because clinical trials are beginning to address the telomerase function in cancer, marketable agents may be less than a decade away. However, such treatments may prove to be too dangerous. Only time and lengthy research efforts will provide answers.
It is too early to predict large-scale improvements in cancer cure rates, but such advances are becoming ever more possible. The prospect of favorably influencing aging is even further in the future because the cancer problem must be solved first.
Ethical Implications: This research is tedious and time-consuming because extreme care must be taken to assure that no human subject is exposed to a risk greater than the expected benefit from the experimental treatment. In addition, all subjects must receive the most effective treatment known at the time, so the experimental agent must be added to one test group that is already receiving state-of-the-art treatments so the two groups can be compared for results. Before any clinical trial is approved, all of these provisions are meticulously examined by a committee known as the Committee on Medical Research Ethics or a similar title. Every medical research institution has such a standing committee.
Limitations
The limitations of the experimental methods used to unlock the mechanisms of action of telomeres are diminishing with the arrival of ever more efficient techniques of characterizing DNA such as polymerase chain reactions, microarray assays, and ligand-based reactions. They are, nevertheless, considerable in terms of cost, complexity of hardware, and the amount of basic knowledge needed to begin exploration.
The limitations of any new medical treatment reside in the unpredictable complexity of living organisms. Effective medical treatments are rarely, if ever, completely risk free. Estimating the risks and balancing them against the possible benefits is a tedious process that entails multiple clinical trials with large groups of individuals with and without the disease in question. Risk estimation begins by testing treatments first on laboratory animals. If the animals do well, the agents may then be tested in healthy human volunteers under highly exacting conditions to minimize the risk of damage. Finally, individuals with the targeted disease or condition are tested under equally exacting safeguards. Only then may the FDA approve a treatment for general use.
Future research
Later events in cancer research, after the initial discovery efforts have created a substantial knowledge basis, may identify the tumor types and the patient populations in which each potential anti-cancer agent will be effective. This research is tedious and time-consuming because extreme care must be taken to assure that no human subject is exposed to a risk greater than the expected benefit from the experimental treatment. Effective slowing of the aging process appears to be a more distant prospect because of its complexity and the vast number of events associated with aging, all of which must be better understood before interventions are undertaken.
Author information
This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).
Bibliography
Bartek J, Bartkova J, Lukas J. DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene. 2007 Dec 10;26(56):7773-9.
Calcagnile O, Gisselsson D. Telomere dysfunction and telomerase activation in cancer--a pathological paradox? Cytogenet Genome Res. 2007;118(2-4):270-6.
Deng Y, Chan SS, Chang S. Telomere dysfunction and tumour suppression: the senescence connection. Nat Rev Cancer. 2008 Jun;8(6):450-8.
Genetics Home Reference. .
Harley CB. Telomerase and cancer therapeutics. Nat Rev Cancer. 2008 Mar;8(3):167-79.
Kumar R, Lal N. PET in anti-cancer drug development and therapy. Recent Patents Anticancer Drug Discov. 2007 Nov;2(3):259-63.
Martien S, Abbadie C. Acquisition of oxidative DNA damage during senescence: the first step toward carcinogenesis? Ann N Y Acad Sci. 2007 Nov;1119:51-63.
Moon IK, Jarstfer MB. The human telomere and its relationship to human disease, therapy, and tissue engineering. Front Biosci. 2007 May 1;12:4595-620.
National Human Genome Research Institute (NHGRI).
Natural Standard: The Authority on Integrative Medicine. .
Parkinson EK, Minty F. Anticancer therapy targeting telomeres and telomerase: current status. BioDrugs. 2007;21(6):375-85.
Phatak P, Burger AM. Telomerase and its potential for therapeutic intervention. Br J Pharmacol. 2007 Dec;152(7):1003-11.
Shawi M, Autexier C. Telomerase, senescence and ageing. Mech Ageing Dev. 2008 Jan-Feb;129(1-2):3-10.
Tallen G, Soliman MA, Riabowol K. The cancer-aging interface and the significance of telomere dynamics in cancer therapy. Rejuvenation Res. 2007 Sep;10(3):387-95.
T?rk?nyi I, Aradi J. Pharmacological intervention strategies for affecting telomerase activity: future prospects to treat cancer and degenerative disease. Biochimie. 2008 Jan;90(1):156-72.