Some weeks ago I gave birth to a child after being pregnant for more than four years. The birth was postponed several times, but finally it came; along with 12 brothers and sisters, and with more than 1,000 parents. Also, I am a man, so you might have guessed it: it was not an ordinary child. It was an article in the scientific journal Nature Genetics, and it was about the mapping of the gene coding for telomerase (!?).
This gene is very exciting for many reasons, and that was the reason why we -- four years ago -- decided to map it. Yes, what we did was really a kind of mapping. If you compare the human genome, the complete collection of DNA in all your cells, with the planet earth then you have the picture of the magnitude. As each landscape can be positioned with latitude and longitude, each gene can be positioned with chromosome number and position within the chromosome. The gene coding for telomerase -- TERT (apologies for the pronunciation, but it is an acronym for Telomerase Reverse Transcriptase) lies on chromosome 5, and stretches from position 1,252,000 to 1,297,000.
TERT is interesting because it codes for the protein which elongates your telomeres, the tips of the chromosomes. Every time a cell divides, it has to copy its DNA to each of the daughter cells. For technical reasons, the outermost tips of the chromosomes cannot be copied. Therefore the cell has to have a buffer of useless DNA at the chromosome tips, which it can afford to lose without losing important genetic information. This "useless" DNA is telomere DNA, and when it becomes very short, the cell is old and grey, and cannot divide anymore. Some therefore describe the telomere DNA as a "multi-ride ticket," slowly being used at each cell division. Luckily, our stem cells can circumvent this fate. Otherwise life on earth as we know it would be impossible. Telomere shortenng is a problem faced by all organisms on our planet. It is really that fundamental. Stem cells have to divide many more times than normal cells, so they can actively elongate their telomeres. For this, they use the protein from TERT; telomerase -- the fountain of youth; at least for the stem cells which stay forever young.
Unfortunately, cancer cells have hijacked this trick. They can divide forever -- and this is exactly one of the problems with cancer cells. They use unfair tricks to keep dividing. These and much more insights were the reason why the Nobel prize 2009 was given to Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase.
Prior to our efforts, several papers of cancer risk and genes reported signals coming from this region of the genome. Signals -- what does that mean? The genome from each individual looks a bit different, and if you compare the small genomic variations in cancer patients with the variations in individuals without the disease, you can measure whether certain variations are more frequent in one of the groups. Since the genomic position of all variations is known, you can locate each signal. And some signals thus came from the vicinity of TERT.
So it all came together: a fundamental biologic mechanism, which might have something to do with cancer, and some tantalizing signals from previous reports. When we got the opportunity to examine more than 200,000 cancer patients and healthy controls, we decided to look at a lot of genetic variants in TERT. This is the technical background for the term "mapping." Furthermore, in my own laboratory and in Cambridge, U.K., we had measured the length of the telomeres in the DNA from many of the individuals.
Our article got the title: "Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer." Our idea before the project was more or less straightforward: The previously reported cancer signals from the part of the genome where TERT is situated were probably due to disturbances in the telomerase regulation of telomere length.
We were in for a surprise: After analyzing the many data, we could define three regions of TERT:
Region one had something to do with telomere length and some subtypes of breast cancer. Region two had something to do with telomere length, breast cancer and a subtype of ovarian cancer. Region three had nothing to do with telomere length, but with subtypes of breast cancer. Another study of prostate cancer and TERT was published the same day and could also define the same Region two as we did. Their puzzling finding was that the variant we found to infer increased risk of breast cancer and ovarian cancer, was protective for prostate cancer. When we looked in detail in the cellular engine room dealing with telomerase, things got even more confusing.
We comfort ourselves with an old saying stating that "good science sometimes provides more new questions than new answers to old questions." In that respect, our scientific report is really good!
So, after four years of work with this area of the genome coding for telomerase, what have we learned? At least we provide convincing (in our minds) evidence that the TERT gene is important for many cancer diseases as well as for regulation of telomere length. At the same time, we dismiss the attractive hypothesis that there is a straight forward pathway between changes of telomerase function, telomere length and cancer risk. This is really a pity from an aesthetic point of view, but sometimes biology, and especially cancer biology remains complicated.