I was living in Baltimore in the 1970's. Located on the campus of Johns Hopkins University, a few hundred yards from where I was working at the time, was a branch of the Carnegie Institute, a world famous research establishment. After attending one of the frequent seminars that was being presented there, I passed some time discussing science with one of the staff scientists. His laboratory specialized in studying cells in culture, and we were talking about a recent publication of Leonard Hayflick that had been making quite a stir. Hayflick claimed that if human cells are placed into tissue culture they will divide only a fixed number of times - about 60 cell divisions - after which they will remain alive, but will no longer be capable of mitosis (the Hayflick limit). In other words, normal human cells have a limited proliferative capacity. My colleague in Baltimore dismissed this as nonsense. He told me that Hayflick didn't know how to properly treat his cells. If only he would have added the appropriate goodies to his culture media, the cells he was studying would have gone on to replicate forever. "Furthermore," he said smugly, " if Hayflick is right, that would mean that something is slowly wearing out, division after division. Can you imagine what that could be?" At the time, no one could. But Hayflick was right. Most normal human cells can only divide a limited number of times. And his observation has profound implications for cancer and aging.
It turns out there is something being lost every time a cell divides in humans and most other higher organisms. It's something that serves as a means of counting because it occurs at every cell division. The counter works because of a limitation of the enzyme that carries out DNA replication – DNA polymerase. For reasons beyond the scope of this post, every time linear DNA copies itself, a small chunk – 50 to 100 bases – is lost at its ends. As you might imagine, that would pose a severe problem, especially for cells that need to divide many times. The shortening of chromosomes appears to be the mechanism that accounts for the Hayflick limit.
Of course most cells need to divide many times during embryogenesis and stem cells must continuously divide to make up for cell death. How do they get around the limits of imposed by the failings of DNA polymerase? The answer, in a word, is telomeres, structures found at the end of the chromosomes of almost all creatures (many bacteria and mitochondria have circular chromosomes without ends and thus avoid the problem). Telomeres were first discovered by one of the giants of biology, Barbara McClintock, a woman whom I was fortunate to meet briefly shortly after she was awarded the Nobel Prize in Physiology or Medicine in 1983. McClintock found that when the chromosomes of corn had somehow lost their normal ends, they fused, end to end, with each other. She reasoned that the termini of unbroken chromosomes must bear structures that prevent this from happening. Many years later, it was found that the tips of chromosomes bore thousands of short repetitive sequences. Depending on the creature, these sequences varied from six to eight bases in length. In humans, the sequence of each telomere repeat is TTAGGG. At its very end, as shown in the figure at the right, the DNA in each telomere loops around and attracts a group of proteins that prevents the ends from fusing with each other.
Telomeres are placed on chromosome ends by telomerase, an enzyme, a reverse transcriptase, that adds bases to DNA using RNA as a template. Embryonic and stem cells have lots of this enzyme. As they divide, their telomeres are thereby readily replenished. But after the initial stages of embryogenesis, telomerase activity wanes, and therefore DNA is lost bit by bit from the ends of chromosomes at each cell division.
What has this to do with cancer? If you've read "The Immortal Life of Henrietta Lacks" by Rebecca Skloot, you'd know that HeLa cells, the cancerous cervical cells that were removed from Ms. Lacks' tumor in Baltimore in 1951 and propagated since then in tissue culture in hundreds of laboratories, grow indefinitely. They are illustrative of the fact that cancer cells are immortal, and must somehow avoid the Hayflick limit. One mechanism that allows them to do that is to reactivate the telomerase gene. And, something on the order of 90% of all cancers do so. How cancer cells accomplish this reactivation is largely unknown, but the gene offers a tempting target for cancer therapy because of its central role in maintaining telomere length. However, there might be a trade off. If somehow or other a drug was found that stopped telomere extension, it might also stop the normal replenishment of telomeres in stem cells. That in turn, might affect aging, since stem cell renewal probably plays an important part in keeping us healthy. Some scientists have taken the opposite tack - they suggest increasing the level of telomerase so as to buttress the ability of stem cells to churn out fresh tissues in old age. In other words, to suppress aging. But of course, this opens up the possibility of encouraging the growth of tumors.
Well, I've finished with my overview of cancer biology. Now on to the final topic: the use of immunotherapy for the treatment of the disease.