ICHG: Queen takes on Dr Jekyll and Mr Hyde

It is not often that we are privileged to hear from someone that has created an entire new field in molecular biology. One of the keynote speakers at the ICHG is just such a person, and she also happens to be an ex-Aussie.

Professor Elizabeth Blackburn will present the latest research on telomerase, a complex and crucial cell regulator that she and colleagues identified some 21 years ago. Telomerase controls the 'ageing' of our chromosomes by protecting the telomeres, or bits of DNA on the chromosome ends. It is now known to play a critical role in both normal cell growth and in cancer, and is probably the reason that Dolly the sheep did not live long enough to celebrate her 10th birthday this year.

Blackburn describes this molecule as the "the Dr Jekyll and Mr Hyde" of cells - it helps us to live to our three score and more, but too much of it in the wrong cells is bad news.

Telomeres are simple DNA sequences found at the ends of chromosomes in almost every eukaryotic cell. They have been likened to the aglets on the ends of shoelaces - they stop the chromosomal DNA from fraying over time until eventually it cannot do its job.

If too short, telomeres fail to protect chromosomes from the inevitable damage that occurs during cell division and the cell is told to stop multiplying in a process called cell senescence. Average telomere length correlates with age, particularly in humans.

Telomerase, on the other hand, is the enzyme that replicates and stabilises telomeres, thus regulating the genetic lifespan of a cell and protecting the genome for generational transfer. Telomerase is an intriguing enzyme in that it comprises an RNA component, which acts as the template for synthesis of the telomere DNA by reverse transcription, and a protein reverse transcriptase.

Usually dormant in non-dividing adult cells, telomerase remains active in all renewing cells such as blood cells, cells of the gut, skin and hair follicles. However, this enzyme also plays a role in uncontrolled cell proliferation, and is abundantly active in 80 to 90 per cent of human cancer cells, allowing the cells to become immortal and never die.

Unexpected functions

In her presentation at the ICHG, Blackburn will focus on the key roles that telomerase plays in cancer. In particular, new research by her group and others points to unexpected functions of telomerase in cancer progression that are outside of its role in telomere capping and maintenance.

In published and soon to be published work, Blackburn's group turned down telomerase in mouse and human melanoma cells using short interfering RNAs (siRNAs), and to their surprise, the cancers rapidly stopped growing (within four days), without telomere shortening or DNA damage.

The overactive glucose metabolism typical of melanoma was back to normal and the cells' gene expression profile reflected an inhibition of metastasis and not one of telomere-shortening.

"The cool thing was that this property of the cells changed their invasiveness ... so they were happily growing and dividing ... but they could not spread," Blackburn says. "Spreading of melanoma, especially to the lungs, is the thing that causes death."

This lead is now being pursued by teams of researchers, including biotechnology firms such as Geron and Amgen and pharmaceutical giants Novartis and Boehringer Ingelheim, to develop cancer therapies. The challenge is to unravel the function of telomerase in this context.

"Basically we don't know yet how this is working," Blackburn admits, although she favours the theory of the cells going into some sort of 'stress response' following a sudden reduction in the characteristically high levels of telomerase activity found in cancer cells. She likens it to a heroin addict suddenly being deprived of the drug and going cold turkey.

In her keynote address, Blackburn will give an insight into how this property might be exploited to block cancer progression. "We think it would make the most sense to use it in combination with other drugs that work on other aspects of cancer cells," she says.

Queen of telomerase

Born in Tasmania (somewhat fittingly at the southern tip of Australia), Blackburn completed a bachelor and masters in science at the University of Melbourne before gaining a PhD from Cambridge. Her work there with double-Nobel laureate Fred Sanger started as an interest in the basic mechanisms of DNA and led to a lifelong and groundbreaking career focused just on the ends.

From the UK, she moved to a postdoctoral position at Yale, where she made her first landmark finding in identifying telomeric DNA sequences from a pond organism called Tetrahymena, as a series of tandem repeats comprising a simple nucleotide sequence. Prior to this, all that was known of telomeres was that they shortened over time and acted as a type of biological ageing clock.

In 1978, she took up a faculty position at the University of California, Berkeley, to continue her work on telomeres. Soon after, she showed that telomeres from Tetrahymena could be substituted by telomeres in yeast. This work was published in Cell and remains one of her most highly cited papers.

"(It) suggested that there was something very fundamentally conserved about telomeric DNA," she says and represented an extremely important finding for biomedical science, with significant medical implications.

In 1985, she and graduate student Carol Greider published their seminal work, also in Cell, identifying the enzymatic activity responsible for maintaining telomere sequence and length, namely telomerase, and subsequently that this enzymatic activity is conserved from yeast to humans. In the early 1990s, Blackburn moved to UC San Francisco, her current home. She became a US citizen in 2003.

The body of her research work is substantial, evidenced by a long list of original articles, contributions and reviews, but more so by the quality of the journals in which she has published and by the 'generations' of scientists that her lab has produced. Interestingly, the field of telomere research is made up of 50 per cent women, a statistic surely influenced by the mentorship of Blackburn.

Unlocking the secrets

She is also a strong advocate for the freedoms and responsibilities of science as a profession, and one that is separate from politics. In 2004, Blackburn's appointment to the US President's Council on Bioethics was not renewed, causing outrage among scientists in North America and elsewhere.

The move was seen as a political exercise in response to Blackburn's public and strong opposition to the government's refusal to discuss therapeutic cloning and human stem cell research. When asked about the decision at the time, Blackburn told USA Today, "I don't feel martyred; I wear it as a badge of honour".

It seems then that telomerase holds more secrets than first suspected, and the 'Queen' of telomerase still marvels at the new insights and challenges presented 21 years later.

Unlocking these secrets may not only lead to innovative therapeutics for cancer, but may also 'cure' at least some of our cells of ageing.

For now, Blackburn is looking forward to what "looks like a great meeting" in August and to re-visiting Australia.

"Some of my family will be coming up to Brisbane to see me, escaping the weather of Melbourne and Tasmania to come to the sun and warmth and the good food. "There are so many questions to be answered; it's a very exciting feeling. I'm kept young by telomerase, but for completely different reasons."