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A Walk Through the Valley of Cell Death

Dr David Vaux

Dr David Vaux

By Barry Leviny

After three decades, David Vaux’s initial research into apoptosis has led to clinical trials of a potential treatment for leukaemia.

Many of us, if we’re honest, would like to help find a cure for cancer, or at least a form of it. I’ve recently been talking to someone who may have done just that. It was a long, complicated road and I was keen to hear how he did it.

After finishing medical school, Dr David Vaux embarked on a PhD supervised by Prof Jerry Adams, head of the Molecular Biology Unit at The Walter and Eliza Hall Institute (WEHI), Australia’s oldest medical research institute. One day, Adams gave Vaux a tube containing the DNA for a gene called BCL2. He didn’t realise it then, but his work towards a new treatment for a form of cancer had begun.

First, some background. Each chromosome is a double-stranded molecule of DNA that, if stretched out, would be more than 1 cm long. Because chromosomes are so thin, they sometimes break, but our cells usually do a good job of stitching them back together again. Sometimes, but very rarely, two chromosomes happen to break at the same time, and the cell joins them together the wrong way around. The technical term for this is a “chromosomal translocation”.

Researchers in the US noticed that in almost every case of a particular type of blood cancer, the malignant cells had a translocation involving chromosome 18 and chromosome 14. Other scientists found a gene at the broken end of chromosome 18 where it was attached to chromosome 14. They called this gene BCL2, and they wondered if this translocation switched on the BCL2 gene and caused the normal white blood cell to become cancerous.

Adams set Vaux the task of figuring out whether too much BCL2 causes a cell to go bad. It was the late 1980s, and some cancer genes had already been identified. These were genes that normally caused cells to proliferate, but damaged genes could cause cells to grow out of control to form a tumour or a leukaemia. Vaux wondered if BCL2 could do this, so he put the gene into cells in tissue culture and switched it on.

Nothing happened. BCL2 didn’t make the cells grow and proliferate. “I did the experiment again and again, watching the cells for any signs of an effect,” Vaux says. He never did see any growth caused by BCL2, but eventually he did notice something. The control cells that were not given BCL2 all died within a couple of days. While the cells that had BCL2 were not proliferating, they were still alive. “Therefore it seemed that BCL2 didn’t act like other cancer genes, namely to drive cells to grow and divide. It appeared to just allow cells to stay alive.”

Some more background. Prof John Kerr, a pathologist from Queensland, knew that about a million cells in our bodies divide every second to make a million new cells, but the same number must also be removed so that we maintain the right number overall. In 1972 he named this process of cellular self-destruction “apoptosis”.

Cell death is a very important part of life, right from the very earliest stages. When a baby’s hands are formed, for example, they first look like little baseball mitts. Later, some of the cells die back, allowing the fingers to separate.

It is very important that apoptosis is carefully regulated so that we can get rid of the cells we don’t want yet keep the cells we need. We don’t want our brain cells to activate their self-destruct mechanisms, but it would be good to get rid of cells that are damaged or infected.

However, because no one knew the molecular mechanism for apoptosis, or thought cell death was relevant to human disease, few researchers were interested in it, and even fewer realised the significance of Kerr’s work. That all changed with BCL2.

Vaux showed that the function of BCL2 was to prevent cells from destroying themselves. BCL2 was therefore the first component of apoptosis to be recognised. “Because chromosome translocations that switch on BCL2 were associated with certain cancers, it became apparent that failure of apoptosis – cells not dying when they should have – could lead to the development of cancer in humans,” Vaux says.

Suddenly, interest in apoptosis exploded. In the early 1980s there were only a dozen or so scientific papers published each year that mentioned the term “apoptosis”, whereas now more than 25,000 new ones appear each year.

It was clear that too much BCL2 could allow cancer cells to survive when they shouldn’t, but how it worked, and how it was regulated in normal cells, was still mysterious. To find out, Vaux needed some help. He got this from a tiny roundworm called Caenorhabditis elegans. These are less than 1 mm long but Vaux says that “scientists love them because they hatch only 14 hours after fertilisation and they die of old age when they’re only two or three weeks old”.

Yet more background. Sydney Brenner, John Sulston and Bob Horvitz won the 2002 Nobel Prize in Physiology or Medicine “for their discoveries concerning genetic regulation of organ development and programmed cell death” using C. elegans. As it grows from a single fertilised egg cell, the worm produces exactly 1090 cells in its body, but the fate of 131 of these cells is to die by a process they called “programmed cell death”.

Furthermore, Horvitz’s lab had generated mutant lines of worms in which these 131 cells failed to die, and they were working to identify the genes involved. In other words, they had a model organism where they could genetically study a cellular self-destruction process.

However, at the time there was nothing to indicate there was anything in common between the mechanism for programmed cell death in the worm and the mechanism for apoptosis of human cells. After all, “the common ancestor between nematodes and humans existed over 600 million years ago,” Vaux explains.

At Stanford University, Vaux continued to work on the human BCL2 gene, but not in human cells. He put the human BCL2 gene into some C. elegans worms, turned it on and looked to see if it would affect programmed cell death during worm development. In the worms that made human BCL2 protein, two- thirds of the cells that normally died during development instead survived. This meant the human BCL2 protein was able to interact with the levers and gears of the worm’s self-destruct mechanism to turn it off.

This revealed that the mechanism for apoptosis of human cells was more or less the same as the mechanism for programmed cell death in the worm, and this mechanism had been conserved through evolution. It also meant that to find out how BCL2 worked in human cells you could look for the human counterparts of the genes for programmed cell death in the worm.

Horvitz’s lab showed that the worm had a gene called CED-9 that inhibited cell death. Two years after Vaux’s experiment, they cloned the CED-9 gene and found that its sequence was similar to human BCL2. They later found that a worm protein called EGL-1 promoted programmed cell death by binding to, and inhibiting, CED-9. Humans also have a number of EGL-1-like proteins that can block BCL2, allowing apoptosis so that cells die when they’re supposed to.

Vaux describes the logic. “Because the genetic accidents leading to production of too much BCL2 could cause leukaemia, a drug that acted as a BCL2 inhibitor, in the same way as the human EGL-1-like proteins, might be able to allow the leukaemia cells to undergo apoptosis”.

To try to make such a drug, in 2006 scientists at the pharmaceutical companies Abbvie and Genentech collaborated with researchers at WEHI to develop a drug that would inhibit BCL2. The idea was that a BCL2-blocking drug would stop BCL2 from inhibiting the cancer cell’s self-destruct mechanism, and allow cancer cells that were being kept alive by BCL2 to die by apoptosis.

This drug now goes by the name veneto­­clax, and patients in Australia were the first to receive it, initially as part of a clinical trial. It is still early days, but there have been encouraging results treating chronic lymphocytic leukaemia in humans, and was recently approved by the US Food and Drug Administration and the Therapeutic Goods Administration in Australia. There are ongoing trials to see if it can be combined with other treatments, and whether it can be used to treat other kinds of cancers.

While the genesis of this new drug was in the late 1980s, it didn’t appear as a tested, approved product until the late 2010s. For about 25 years there was nothing definite to show for the work, and there was always the chance of a roadblock to further progress at any stage. It was a piece of pure, basic research that has paid off.

Early in 2017, in one of the biggest medical research deals in Australian history, WEHI sold some of its rights to future royalties from sales of the drug to put toward funding other research.

Barry Leviny is host of The Uncertainty Principle on Vision Australia Radio.