1998 Australia Prize
PROFESSOR ELIZABETH BLACKBURN (USA)
Dr Elizabeth Blackburn's identification of an enzyme crucial to the successful replication of chromosomes in cell division is hailed as one of the most important discoveries in the field of molecular genetics.
Before Dr Blackburn's discovery of telomerase in 1980, it was thought that a dividing cell made perfect copies of all its genetic material. It was known that there was an army of enzymes in each cell whose job it was to execute this replication.
However, the enzyme Dr Blackburn discovered was a one and crucial to the division process. Named telomerase, it enables DNA at the capped end of chromosomes to replicate fully. It was a discovery that finally allowed geneticists to understand the way chromosomes replicate.
Blackburn told of a major quirk in cell replication: crucial though they are to health, without telomerase, cells cannot copy the caps of their chromosomes.
The capped ends of chromosomes are called telomeres, which are necessary to maintain our genetic blueprints in good order, particularly during cell division.
"Genetic material can get very messed up if you do not have a special cap on the chromosomes," said Blackburn. She used a shoelace analogy to illustrate "If you don�t have those little tips on both ends of your shoelace, the shoelace frays," she said. Even worse, without telomeres, broken chromosome ends combine with any other end they find and that is not good for the health of the organism. It's as though someone ties your shoe laces together and makes you fall over."
In research, which is pan of her Australia Prize-winning work, Blackburn and her student Carol Greider at the University of California Berkeley, applied themselves to the question of how those caps, the telomeres, were replicated.
There had been clues that something quite strange goes on in this region of the chromosome. Previously, Blackburn and colleagues had taken a telomere from a pond organism and put it into a distantly related organism: baker�s yeast.
Normally, unions between such organisms do not work, but the yeast cell adopted the pond organism's telomere as its own and added its own telomeric DNA to the foreign telomere.
"That didn't happen according to the text books," said Blackburn. "Also, we knew that instead of getting shorter with the division of every cell, the deoxyribonucleic acid (DNA) alternately gets a bit longer, then a bit shorter with the next division, then longer and so on.
"The textbooks didn�t account for that either," she said. "So we decided to look more closely at what we'd found. After many attempts over several months, we put synthetic DNA into a test tube, mixed it with an extract of cells from the same pond organism, called a Tetrahymena. Then we added radioactive DNA to see if it would produce telomeric DNA - DNA was found in the tip of the chromosome. And that�s just what it did."
Blackburn said she knew she was observing a new enzyme at work. "It was 'Eureka' when we looked at the DNA made in the test tube and saw that the pattern at the ends of chromosomes - a sequence of base chemicals repeated over and over - was exactly right for telomeric DNA," she said.
They worked out that the new enzyme was copying the ribonucleic acid (RNA) template of telomerase over and over again. It's a dull sequence, but a crucial one because it attracted a lot of proteins to it which helped create the caps at the ends of DNA.
The enzyme she discovered was first named telomere terminal transferase. "But after we'd said that name a few times, we got a little tired of it, so we called it telomerase," said Blackburn. "The name stuck."
Questioned about the quirky system that produced a one-off like telomerase, Blackburn conceded that nature doesn�t always evolve in the best possible way. "But it does work." she said. "In the case of telomerase, there's a defect in the evolution of the cell's replication machinery.
"Telomerase is an independent mechanism. It adds DNA to the ends of chromosomes to take care of this sad glitch. It saves the chromosome�s bacon. It�s not elegant or clever. In fact, it�s kind of clumsy. But it works and has done so for billion of years for every creature, apart from bacteria. They have circular DNA."
Elizabeth Blackburn went further into the biology of telomerase. "It's RNA plus protein which together become a crude little copying machine," she says. "It's thought to be one of life�s ancient relics which got fossilised into our cells. Had it been useless, it would have been selected out."
"Cells have much more sophisticated replication machines than telomerase," said Blackburn. Telomerase is a Model T Ford compared with the other DNA replication machines - the Ferarris - in the cell.
Dr Blackburn's discovery of telomerase prompted a flurry of new work in cancer research. "Telomerase is not normally very active," she says, �But in cancer cells it just goes wild and yet telomeres in cancers don�t get very big and that indicates that there's something that reins telomerase in. We believe the telomere repulses telomerase most of the time because telomerase wants to make the telomeres ever longer."
According to Blackburn, the basic building blocks of our cells - proteins, enzymes, chemical bases and the like - are a ramshackle concoction of the old, the new and the ancient. "But while it may appear cobbled together, it's a system that works," she said "Because of their disparate origins, the relationship between these parts is not always clear. And while we�re creatures of logic, perhaps our system, human biology, is not logical."
"In biology, we currently often have a linear way of thinking," says Blackburn. "You have a cause and that produces an effect and so on. It's a big task to rationalise a complicated cell in which a thousand different genes produce thousands of different molecules at once. We need better ways to analyse complex reality. Maybe we need better mathematical systems, better computer systems, a new generation of ways of thinking about these problems. It�s an exciting challenge.
Blackburn was confident that we are capable of understanding the processes of our cells. "However, at the moment, she said, "We're still groping for answers."
Dr Blackburn said that when you break new ground in biology, a thousand new questions rear their heads. "After we discovered telomerase," she says, "we immediately wanted to know how the enzyme worked, its relationship with telomeres, its history, how cells control it. They're all large questions."
Elizabeth Blackburn's research is currently focussed on the very tip of the chromosome. "We think the last few repeated DNA , these sequences on the cap, may be the key to understanding what the cap is doing," she said.
Australian-born and educated, Elizabeth Blackburn completed an undergraduate degree and a Masters in biochemistry at Melbourne University.
She was awarded her PhD at Cambridge University and in the mid-l970s, moved to the US with her husband, John Sedat. She later took a position at the University of California, San Francisco where she is now Professor and Chair of the Department of Microbiology and Immunology, and Professor in the Department of Biochemistry and Biophysics.
Dr Blackburn said she's very proud and excited, and feels very Australian, being named one of the winners of the 1998 Australia Prize. "I've always had the family connection with Australia, but professionally, my life has been in the US," she said. The Prize has given me a true professional connection with the country of my birth and that's a real thrill."