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Calvin Harley Calvin Harley as seen on Never Say Die: The Clock of Life

Click on Calvin's photo to read a brief bio.



q Congratulations of your ground-breaking research! How did you make the discovery of telomeres and their function in cells? Were you looking for this specifically, or was it a something you discovered in the course of other research? (Question from Vivian H.)

A We were looking for it specifically. The idea that chromosome ends might shorten with cellular aging goes back to the early 1970s when a Russian theoretician proposed the concept as an explanation for the "mitotic clock".

At about the same time, Jim Watson (of Watson and Crick fame) independently recognized that chromosome ends need a special mechanism for complete replication. I was interested in testing the idea in 1975, but it was not until the late 80's that it became possible to do definitive experiments. Work I did while at McMaster University with scientists at Cold Spring Harbor Laboratory, and later work that we did at Geron Corporation over the past 5-10 years, has proven the model to be correct.



q In another story on Never Say Die, Alan Alda asked Cynthia Kenyon why the cells have a built-in "clock of life," i.e., a mechanism to limit the number of times they divide. She did not know. Do you have any ideas about this complex question? (Question from Tom D.)

A Although nematode worms clearly age, it is not clear that they have a "clock of life" at least not for dividing cells. Adult nematodes in fact do not have any dividing body (non-reproductive) cells. Thus, we believe that the aging of nematode worms occurs by a very different mechanism than that of humans, at least with regard to tissues in which cells divide. The reason a "clock of human cellular aging" evolved is that for long-lived organisms like us, there needs to be a very efficient set of "anti-tumor mechanisms". Programming a finite lifespan into the body cells appears to be just one such mechanism to limit the growth of tumor cells. During the course of primate evolution, the age-related problems of telomere loss in normal (non-tumorous) tissues would not be "seen" by evolutionary forces to any significant extent since very few individuals live to see "old age". Thus, there could be strong selective pressure for a finite lifespan of body cells to reduce the probability that rapidly dividing mutant cancer cells would survive long enough to kill us. The deleterious, age-related consequences of this are just a late-acting side effect of the beneficial impact of telomerase repression in early development.


q It was exciting to see the amazing results of the experiment where you injected the telomerase gene into eye cells. Have you had any opportunity to try inserting the telomerase gene into any tissues of a living animal yet? (Question from Jean)

A We are working on it. We believe that if this is done efficiently and safely that it will lead to new treatments for diseases such as macular degeneration, immune failure, atherosclerosis, liver cirrhosis, skin disorders, and others.


q I was touched the plight of children with Progeria. Is there a way your research can be applied to help reverse the shortened telomeres of the children with Progeria? If so, what will the effect be? (Question asked by several viewers)

A Applications of telomerase therapy to genetic disorders like Progeria and others are a possibility. Further research on developing effective and safe means of delivering or activating telomerase needs to be done, which is a major focus within our company.


q Until we can develop a true "long-life pill," is there anything we can do in the meantime with diet, exercise, vitamin supplements, etc. to enhance the body's production of telomerase? (Question from Ralph in AZ)

A Not that I'm aware of. But please note that we are developing telomerase therapy not for "long-life" per se, but for the treatment or prevention of disease.


q It is stated in the program that mouse telomeres are longer than human telomeres. Why do mice not live longer than humans? (Question from willib1)

A Many mice die of cancer or cancer-related complications in old age. Whether long telomeres and their more liberal expression of telomerase contributes significantly to the much higher frequency of cancer in mice than in humans is not really known. Other, non-telomere related factors could also contribute to their major age-related diseases. Standard laboratory mice are not necessarily good models of human disease and longevity. A much better model is emerging in the work of Ron Depinho and others with the "telomerase knock out" mouse. In these telomerase-negative mice, telomeres do not significantly shrink with time and become critically short after 5 or 6 generations of inbreeding, at which point age-related pathologies linked to telomere loss become apparent. The 5th or 6th generation telomerase null mice have telomeres similar in length to humans.


q On the show we saw your experiment inserting the telomerase gene into human eye cells, and another experiment where it was used to increase immune system function. Do you know yet if the telomerase gene will work equally well to stop the aging of all types of cells, or does it show more promise with specific types of cells? (Question from Susan)

A In the laboratory, telomerase seems to work well in all dividing cells which reach a proliferative crisis due to critical telomere loss. In humans, the best "targets for ultimate therapeutic interventions will likely be cells in areas of chronic stress which show evidence of significant telomere loss and loss of normal replicative capacity contributing to life-threatening conditions.


q Will the combination of your company's recently issued nuclear cloning patents and potential NIH embryonic stem cell funding help other companies advance this important research and bring us to viable products or therapies sooner? (Question from Mark)

A We expect that the issuance of nuclear transfer patents and federal funding for research on embryonic stem cells will accelerate the development of therapies. This could occur through more rapid advances at Geron or through corporate interactions between Geron and other companies and/or the research community.


q Do some people have longer telomeres? Is there a standard? (Question from Carrie R. chemistry student at North Middlesex Regional High School, Townsend, Mass.)

A There is some natural variation between individuals in telomere length, as expected, and there is an average or standard length we can assign for genetically normal individuals of any given age. Interestingly, genetic mutations can give rise to individuals who are born with shorter telomeres and/or lose telomeres at a faster rate than normal individuals. Cells from these patients tend to have shorter average lifespans in the laboratory.


q I am amazed by the leaps and bounds that the field of biotechnology has taken during the last ten years. During the PBS show, a comment was made that a cell can only divide approximately 50 times before the telomeres "wear out." This number seems quite small considering the amount of dead skin that falls off a normal human. The only explanation that I can derive is that the number is really 2 (two) to the 50 (fiftieth) power number of cells or 1,125,900,000,000,000. This would be the total number of cells if one cell divided into two and all subsequent generations also divided into two with fifty iterations of the process. Please advise on my assumptions and conclusions. Thanks. (Question from Ross)

A Your math is correct, assuming cells divide exponentially. In some cases they do, in some cases they don't. Your number of 1.1259 x 10^15 cells for only 50 doublings translates to about 10,000 kilograms of cells from EACH starting cell. This is more than enough for a lifespan, given that we are born with BILLIONS AND BILLIONS (a Sagan Unit) of cells in every organ. In most cases, tissues do not use full exponential growth, and very likely highly proliferative tissues like skin and blood need to use transient telomerase expression to slow telomere loss and extend the lifespan of clonal populations of cells.


q Ever since reading an article (which I find that you co-authored) in the January, 1988 issue of SCIENCE, I have followed--as much as a layman can--research being done regarding telomeres and aging. Research into aging, cancer, and other degenerative diseases has the potential to fundamentally change our lives and the basic structure of society. Geriatrics, economics, sociology, politics, education. even fashion design and life insurance will be profoundly changed. I would expect your research to be of profound interest to anyone who is aging. A simple, but vexing question is why do so few people seem to care? (Question from Burkhart)

A I think the number of people who care is gradually increasing. Why so few people cared in the past (and maybe even still), may be due to the fact that people tended to think that the progressive onset of age-related diseases is inevitable--that we couldn't do anything about it. This will change. However, I wish to stress again that we are currently focused on the treatment of cancer and degenerative diseases that severely limit our healthy lifespans, not on "living forever". The prospect for increasing maximum human longevity in the long run might look good theoretically, but we likely have only a fraction of the knowledge we need to do this and it is certainly not practical today.




 

Scientific American Frontiers
Fall 1990 to Spring 2000
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