Aging and Cancer: Are Telomeres and Telomerase the Connection?
Dr. Shay has been a pioneer in relating the fields of aging and cancer research, advocating what is known as the "telomere hypothesis". The principles of this hypothesis are fairly simple. Healthy human cells are mortal because they can divide only a finite number of times, growing older each time they divide. Thus cells in an elderly person are much older than cells in an infant. As a person's cells age they can no longer assist in maintaining and repairing human tissue, and this is believed to be responsible for many of the degenerative diseases associated with aging. Drs. Shay and Wright have demonstrated the molecular mechanism dictating that cells can divide only a finite number of times. They and their collaborators at Geron Corporation demonstrated that the progressive loss of telomeres, the DNA sequences found at the ends of each chromosome, is the biological aging timing mechanism or clock. For the cell, having a long telomere can be compared to having a full tank of gas in your automobile; having a short telomere is like running on empty. Each time a cell divides, its telomeres become a little shorter until the cells simply can no longer divide (e.g., it runs out of fuel).
The question he asked was, in order to extend a cell's lifespan, how can we keep the cell's telomeres long? Dr. Shay and his colleagues found that cellular aging can be bypassed or put on hold by the introduction of the catalytic component of telomerase (i.e., the fuel added to the gas tank to keep the car running)! In the laboratory, cells in tissue culture with introduced telomerase have extended the length of their telomeres. They have already divided for 250 generations past the time they normally would stop dividing, and are continuing to divide normally, giving rise to normal cells with the normal number of chromosomes.
In his earlier work, Dr. Shay found that the enzyme telomerase was present in specialized reproductive cells and in most cancer cells that appear to divide indefinitely. Thus, the gene which codes for telomerase has been nicknamed the "immortalizing gene". Telomerase works by adding back telomeric DNA to the ends of chromosomes, thus compensating for the loss of telomeres that normally occurs as cells divide. Most normal cells do not have this enzyme and thus they lose telomeres with each division. A potential paradox was to explain why the introduction of telomerase did not result in cancer progression in the currently dividing cell cultures. Dr. Shay believes that cancer is caused by the accumulation of several alterations that occur over a lifetime, not just one factor such as an alteration in telomerase. Thus, the single addition of telomerase maintains the "youthfulness" of a cell line, but does not induce it to convert to a cancerous cell. Using the car analogy again, cancer can be considered as a runaway car (i.e., with malfunctioning brakes, accelerator stuck to the floor, steering wheel coming off the column, as well as having an unlimited supply of fuel [telomerase]). Just adding fuel to the car will keep the car running but it will not be a runaway car. Likewise, just adding telomerase to cells will keep them dividing but they will not have the unregulated growth characteristic of cancer cells.
Putting all this together, Dr. Shay's goal has been to understand the cellular and molecular mechanisms of normal aging with the hope that such knowledge could ultimately increase human healthspan if not necessarily lifespan. It is fine if average lifespan is slightly increased due to the application of these findings in the human organism, but he does not expect that telomere biology will explain all or even a large portion of human aging. His recent work is proof that the reason human cells are mortal and grow older each time they divide is because their telomeres shorten. The potential medical implications of this finding are profound: one might take a person's own cells, manipulate and rejuvenate them without using up their lifespan and then give them back to the patient. Thus, by manipulating telomere length one might change the rate of cellular aging and affect degenerative diseases of aging--a truly exciting possibility. Twenty years ago, the assumption that we would remain incapable of altering the aging process, the diseases associated with it, and their consequent morbidity and mortality was appropriate. With this new discovery the implications are staggering. It is becoming clear that our assumption was flawed, and that the aging process itself and age-related diseases may, in fact, be modifiable. Based on these findings, some areas of cell engineering that may be possible in the future include: bone marrow transplants, supplying unlimited skin cells for grafts for burn patients, producing products with cosmetic applications (e.g., to aging skin), extending the lifespan of muscle satellite cells as a mode of gene therapy for muscular dystrophy, improving general immunity (for older patients, patients with AIDS or other blood disorders, in macular degeneration [a leading cause of age-related blindness]).
In addition to the age-related implications of this work, there is also the potential of discovering novel cancer therapies that attack telomerase (the immortalizing enzyme). Dr. Shay and his colleagues believe that cellular senescence acts as a "cancer brake" because it takes many divisions to accumulate all the changes needed to become a cancer cell. Almost all cancer cells are immortal and have thus overcome the normal cellular signals that prevent continued division. Young normal cells can divide many times but are not cancer cells since they have not accumulated all the other changes needed to become cancerous. Thus, in most instances cells become senescent before they can become a cancer cell. Therefore, aging and cancer are two ends of the same spectrum and the key issue is to find out how to make our cancer cells mortal and our healthy cells immortal, or at least longer-lasting and better-functioning. Inhibition of telomerase in cancer cells may be a viable target for anti-cancer therapies while treatments that extend the expression of telomerase in normal cells may enhance lifespan. Overall, Dr. Shay's results suggest that the gene for telomerase is both an important target for cancer and for the treatment of age related disease. The telomerase gene will likely have many important applications in the future of medicine and cell engineering.
The Process of Science
The process of doing research is highly individualized, and Dr. Shay offers some interesting thoughts about science process. He says: First, always work on experiments that you are interested in, and second, work hard. He goes on, "I never believed I was very talented and thus believed that the key to my own survival in science would have to be to work hard, to put in a lot of time on my work". He also didn't become too infatuated with his own experiments. If the data didn't progress within a reasonable amount of time then he turned to a new project. He explains that all too often scientists become bogged down in what he describes as pedestrian aspects of science. He quotes Paul Berg (a Nobel Laureate): "All science is interesting if you study a problem in enough detail. The key question to ask is, 'Is what you are doing important?'." Thus, while some scientists spend their whole lives studying one problem, he says he has always chosen to follow what interests him most and to not get bogged down in the minutiae of the story. This does not mean that you jump from project to project. Rather, let's say that after five years of working on a problem you need to ask yourself if you are making significant progress in understanding some fundamental biological mechanism. If not, then it is time to move on or change your focus. Dr. Shay is motivated as well by the fact that because most of his work has been supported by the NIH (National Institutes of Health), he sees it as his responsibility to be able to communicate to a lay audience why his work is important.
It is interesting to note that there was no direct path from his M.A. and Ph.D. research to where he is presently. When he was a graduate student he worked on the cytoskeleton and was interested in the regulation of microtubules. When he joined the Porter lab in Colorado he shifted to studying somatic cell genetics. Dr. Shay was interested in taking cells apart and putting them back together, and developed techniques to enucleate cells and to separate them into karyoplasts (nuclei) and cytoplasts. The cytoplasts were capable of some motility and this is his original connection to the cytoskeleton. The objective of the project in Boulder was to take tumor karyoplasts and put them back together with normal cytoplasts (and the reverse). Later, he became curious about whether there were non-nuclear aspects of cancer progression, and he became interested in mitochondria and the role of mitochondrial DNA in cancer. He worked in this area for several years at U.T. Southwestern before getting involved in cellular aging work. As it turns out, when he was doing the cell reconstruction experiments at Boulder, Woody Wright, a graduate student with Leonard Hayflick at Stanford was doing similar experiments, although he was combining young nuclei with old cytoplasms. In the late 1970's Dr. Wright came to work in Dallas. For the next five years he worked on muscle development while Dr. Shay continued with his mitochondrial work. Eventually they realized they were interested in the same question, although from a different perspective. Dr. Wright was interested in the cellular mechanism responsible for cell aging, while Dr. Shay was interested in the cellular mechanisms that had to be overcome for a normal cell to become capable of growing indefinitely. Thus, they started a series of experiments that have continued to the present.
According to Dr. Shay, the process of science is not always "gee whiz". He says that he was interested in why it was so easy to get spontaneous immortalization of mouse cells in culture yet almost impossible to do the same with human cells. In the mid-1980's he studied how to immortalize human cells and discovered that there were two independent mechanisms occurring in human cells that prevented immortalization. He goes on: We called these mortality stages 1 and 2 and began to investigate the molecular mechanisms involved in each. During the first five years we discovered that p53 and pRB (tumor suppressor genes) were likely involved in the onset of M1. It wasn't until 1990 that we proposed that telomeres were probably involved in M2. In 1992 we showed that cells that escape M1 continued to grow, but in the absence of telomerase their telomeres continued to shorten. It became more obvious that immortalized cells had to have a mechanism to maintain telomere stability. Telomerase had been discovered by Carol Grieder in 1985 in Tetrahymena, so it was an obvious candidate. However, it wasn't until the cloning of the telomerase catalytic subunit that we were able to test it directly. The Science (1998) paper I would argue is formal proof for the telomere hypothesis of cellular aging. As there were no easy assays to measure telomerase, we developed what is now known as the TRAP assay (a PCR based technique that allows for the detection of telomerase using small tissue biopsies). This progression from the general to the specific was accomplished, as you can see from this brief description, in fits and starts and piecing together a variety of observations, and along the way new methodologies were developed.
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