Is immortality within our reach?

Beth Ashbridge 22 November 2007

Beth Ashbridge illustrates how chemistry and biology can work together to solve the problem of cancerOur understanding of biology is far from complete, so every new discovery resonates through the scientific community invoking fresh motivation and passion for knowledge. Delving inside the cell, we have begun to unravel the complex operations that allow us to function properly. Of more medical interest, however, is what happens when these ‘mechanisms’ don’t work effectively: in particular what causes a cell to become cancerous.

In 1985, Elizabeth Blackburn and Carol Greider announced the discovery of a new biological catalyst, an enzyme they dubbed telomerase, which could extend the ends of chromosomes in cells. “We had to roll up our sleeves, break open the cells and try and find out what this potential new enzyme was that was adding DNA,” commented Dr Blackburn.

But what were the implications of this finding to our understanding of cancer and what progress have we made since then?

Every cell contains a nucleus, enclosing essential components for the cell’s survival. Within the nucleus there are strands of DNA, known as chromosomes, which encode all the information necessary to define a species- they determine what makes a human a human and a dog… well, a dog.

In order to grow and mature, our cells must divide over and over again to generate and replenish every part of our being. As each cell divides, enzymes known as polymerases make a copy of every chromosome within the nucleus. These chromosome pairs separate and go on to make two new cells in a process known as mitosis.

Unfortunately, this process is not perfect, as every cell division results in an incomplete copy being made of the original chromosome: each copy is shortened at the end and subsequently risks losing DNA. Clearly, if every cell division resulted in a loss of vital information, we would soon suffer.

Luckily, the body has adapted to combat this loss by creating telomeres. Telomeres, from the Greek telos meaning end and mere meaning part, are short sections of nonsense code capping the ends of chromosomes, so that after each cell division it is the telomere that is docked, and not the genetic code.

However, these telomeres are not an indefinite buffer, as after several rounds of cell division the telomeres will become so short that a further division would result in a risky loss of essential DNA. The body has evolved to avoid this problem; when the telomere reaches a critical length, known as its Hayflick Limit (after the cell biologist Dr Leonard Hayflick), the cell is programmed to self-destruct, and thereby prevent any further shortening of our DNA sequence.

This clever extension of the chromosome is present in all mammalian species-but what does this have to do with Blackburn and Greider’s discovery mentioned earlier? In reality, not all cells reach their Hayflick Limit and die out. Certain cells are able to mobilise telomerase, an enzyme that can rebuild the shortened telomeres on the end of chromosomes.

Why has the current mechanism of a finite number of cell divisions followed by cell death proved insufficient for our proper functioning? Why does telomerase exist?

The answer lies in stem cells. Stem cells are precursors to every other cell type in the body, from liver cells to brain cells; a constantly dividing stock needed for a lifetime of running repairs. They possess the ability to activate telomerase allowing stem cells to divide indefinitely. Thus, stem cells are classed as “immortal” cells. However, it has been found that cancer cells share this distinction. This makes their numbers difficult to control; they replicate endlessly spreading deadly tumours throughout the body.

The aim of several research groups currently working on this problem, including the Shankar Balasubramanian Group at the University of Cambridge, is to determine the structure of telomerase and how it actually works to mend the ends of chromosomes. For 20 years research has been slow because telomerase is a very tricky enzyme to study: this is largely due to the fact that cells only ever produce a tiny amount, probably because only small quantities are needed at the chromosome level. We know the basic principles of how the enzyme functions, but a complete picture of the mechanism still evades us. It is this detail that is necessary if we are to develop a drug therapy that would deactivate the enzyme, and potentially help us fight cancer.

The World Health Organisation (WHO) predicts that over 11.4 million people will die from cancer in 2030. Telomerase research aims to provide a new insight into fighting this killer by finding innovative ways to probe the telomerase system. The ultimate hope is to develop new therapies that promise to make cancer cells mortal and so control the unruly spread of tumours that plague so many lives every year.