The Prize:
The 2009 Nobel Prize in Medicine or Physiology awarded jointly 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.”
The Science:
What do genome stability, aging, and cancer have in common? All of these processes can be traced back to telomere function.
All cells that have a nucleus—including yours, but also those of all plants and animals, and some single-celled organisms—package genetic DNA in the same format: linear chromosomes. The ends, or telomeres, of those chromosomes have long intrigued biologists as the potential key to remedying disease associated with genetic instability and chromosome degradation.
In the 1930s, Hermann J. Muller and Barbara McClintock (Nobel Laureate, 1983) proved that telomeres are important for chromosome integrity. McClintock showed that without telomeres, chromosomes tend to stick together and sometimes undergo rearrangements that are harmful to the cell.
In 1972, James Watson (Nobel Laureate, 1962) showed that the cellular enzymes that replicate DNA in the cell cannot faithfully replicate telomeres, due to a quirk of DNA replication.
Cells duplicate genomes using a parental genome as a template. As the cell begins to duplicate, the two strands of DNA’s famous double-helix structure pull apart. Each daughter cell ends up with a double-stranded DNA genome: one strand from the original parent strand and a newly synthesized complementary strand. Because DNA replication starts at the centre of the strand, a lagging strand is produced whereby one arm of each of the parent strands doesn’t copy all the way to the end, resulting in telomere shortening. So how does the cell keep from shortening every chromosome every time it replicates itself?
Elizabeth Blackburn discovered the clue to solving this conundrum. Between 1975 and 1977, Blackburn found that the single-celled organism Tetrahymena has telomeres that consist of a number of DNA sequence repeats. Blackburn presented these results at a conference where it caught the interest of Jack Szostak. At the time Szostak was working on linear DNA called mini-chromosomes. He found that these mini-chromosomes rapidly degraded during his experiments when introduced into yeast cells. He couldn’t understand what made the mini-chromosomes different from the linear yeast chromosomes, which don’t decay in the same way. Together, Blackburn and Szostak hypothesized that the two experimental results were connected.
Blackburn provided Szostak with the DNA sequence repeats from Tetrahymena telomeres and Szostak added them to the ends of his mini-chromosomes, which lacked telomere ends. The mini-chromosomes were protected from degradation even though the protective DNA sequence came from a very different organism. We now know that most organisms with a nucleus carry telomeric repeats of almost the same DNA sequence.
In the 1980s, Blackburn and Szostak showed that the number of telomeric sequences at the end of each chromosome differs not only between organisms, but also between the chromosomes of different cells within the same organism. Blackburn and her then graduate student Carol Greider decided to see if they could find an enzyme that could account for these differences in length. They discovered telomerase (telomere polymerase) on Christmas day, 1984.
Telomerase is an enzyme made of both protein and RNA (ribonucleic acid). The RNA component of the enzyme carries the DNA repeat sequence which acts as a template for the lengthening of the telomeric repeat sequence. Telomerase activity allows the DNA polymerase to replicate the parental strand DNA to the end of the chromosome during cell replication. But this process is not always perfect.
Yeast cells with mutations that prevent them from maintaining telomere length grow poorly and eventually stop dividing altogether. Similar observations were made in Tetrahymena. Both of these organisms are single-celled, and under normal conditions can replicate uninterrupted forever. Telomerase function is central to their immortality. What remains to be understood is how important telomerase function is in other organisms that have finite lifespans, like humans.
Greider went to on to found her own research lab and, along with others, discovered that many human cells lack telomerase. In the 1970s, Alexey M. Olovnikov hypothesized that chromosome shortening could explain how some cells age and die. The observation that cells of the human body that eventually die lack telomerase activity appears to support Olovnikov’s hypothesis. Mortal cells are known to divide a finite number of times. Interestingly, their telomeres shorten as they age. Conversely, cancer cells (which are essentially cells that reproduce too well and too quickly) have been observed to display increased telomerase activity.
The Significance:
When telomerase was initially linked to cell immortality, telomerase function became a target for cancer research and research to reverse or slow the aging process. This has led to linking some human diseases to altered telomerase function, including some skin and lung diseases, and congenital aplastic anemia, a type of anemia where the bone marrow does not produce enough cells to replace blood cells.
Overall, the evidence so far favours a model in which telomerase function is a contributor to cancer cell growth, but not one of the initial changes that turns a cell carcinogenic. The connections between telomerase and cancer, aging, and disease are only more complicated than initially hypothesized and have opened up new avenues for research in these fields.
This year’s Nobel Prize in Medicine or Physiology is also significant as it is the first time that two women have shared a Nobel, and the first time an Australian woman has won.
