Transcript

Cell death with David Vaux

Matt Smith:

Welcome to the La Trobe University Podcast. I’ll be your host, Matt Smith, and I’m here today with Professor David Vaux of the Department of Biochemistry and the School of Molecular Sciences. Thank you for joining me, David.

Prof. David Vaux:

Hi, Matt.

Matt Smith:

Now, you study cell death?

Prof. David Vaux:

That’s right. Cell death is the process of cell suicide. So it’s a normal process whereby cells kill themselves. So in your body, every second about a million cells divide in two. So every second you’ve got an extra million cells and so you don’t get bigger and bigger and bigger and end up the size of a planet. A million cells have to be got rid of and the way they’ve gotten rid off is by activating an intrinsic self-destruct program. And I will call that the nuts and bolts, the cogs and wheels and levers of this self-destruct program within cells.

Matt Smith:

Are there two extremes of this? Are there people whose cells don’t self-destruct and people who have too many cells that self-destruct?

Prof. David Vaux:

That’s right. Most of the time it operates perfectly normally and you need a lot of cell death to remove excess brain cells that produced while the baby is developing the womb, but if the cell death process goes wrong then you can end up with different kinds of diseases.

So for example, if there is damage to a gene so that a cell can’t kill itself, then that cell will stay alive and its progeny will stay alive and they will accumulate. They can eventually turn into a cancer. On the other hand, given that every cell has this built-in self-destruct mechanism, you don’t want a million brain cells to commit suicide every second, you know, if you catch a cold.

Matt Smith:

Yeah. What would happen if too many of your cells did commit suicide?

Prof. David Vaux:

If it’s too many cells that die in the brain then that could cause neurodegenerative disease such as Parkinson’s disease or Alzheimer’s disease, or if its heart cells it could decrease heart effort. For example, we know that many cells activate this self-destruct program when they become stressed and one way of stressing cells is by blocking off the blood supply so cells don’t get enough oxygen.

Matt Smith:

So they can be starved.

Prof. David Vaux:

Yeah. So it turns out that when a blood vessel is blocked in the brain, some brain cells die because they don’t get enough oxygen, but some cells die unnecessarily because they become stressed and then they kill themselves. So if we had mechanism of blocking the suicide process, we might reduce the amount of brain damage following a stroke or damage to the heart muscle following a heart attack.

Matt Smith:

So is your research trying to find out how this is triggered?

Prof. David Vaux:

We’re really just trying to work at the mechanism. We’re trying to work at the actual mechanism by which cells kill themselves and then the pathways that regulate that. And once we have an understanding of molecule by molecule of the whole process, then that allows us to develop inhibitors of cell death to stop cells dying when they shouldn’t and things that activate the cell death process so that we can get rid of cells that we want to get rid of, like tumor cells.

Matt Smith:

What form would these inhibitors come in?

Prof. David Vaux:

The inhibitors come in all sorts of forms, but the first step is to determine the mechanism and the mechanisms of most cellular processes are regulated by proteins and the proteins are encoded by the genes. So once we have identified the particular component, then we can work out which other components it binds to, like you can imagine two wheels, no gears, meshing with each other. And once we know the shape of the interaction, the three dimensional structure of those two meshing proteins, we can try to figure out the structure of a spanner to go into works to stop it happening. Now, the usual way of developing inhibitors or drugs that regulate the process is to do a screen for small compounds that bind to these proteins, these components, or to develop unofficial drugs that resemble some of the cellular components.

We don’t ourselves screen for these drugs, but we collaborate with some pharmaceutical companies that have done the screens and we help them analyze new regulators of cell death.

Matt Smith:

Can you tell me a bit about how you got into this field?

Prof. David Vaux:

This all started way back in the late 1980s and it came from some groups in the US who were studying common cancer of the white blood cells called follicular lymphoma. This is a very common sort of malignancy of white blood cells called lymphomas or leukemias. Follicular lymphoma is the commonest one in western societies.

Now, when these scientists looked at the cells in follicular lymphoma, they’ve found that in the malignant cells, two of the chromosomes had been broken and then they are being repaired by the cell but they repaired the wrong way around. So a little bit of chromosome 14 was stuck to the end of chromosome 18 and vice versa.

So because there was close association between this particular chain abnormality and follicular lymphoma, it was hypothesized that there were some sort of cancer gene that was altered by this genetic accident. The chain that was found in follicular lymphoma was called BCL-2 for B cell because these lymphoma cells are called B cells. It’s in the white blood cells to make antibodies – B cell leukemia/lymphoma gene 2 or BCL-2.

So my job as a PhD student was to try and figure out how this BCL-2 or the protein encoded by the BCL-2 gene, how does that promote formation of this kind of cancer. Now, most cancer genes act by stimulating cells or causing cells to proliferate and multiply more rapidly, but it turned out that BCL-2 was different to conventional cancer genes because instead of stimulating cells to proliferate, it stops cells from being able to commit suicide. So BCL-2 became the first component of the mechanism that regulates cell suicide in any organism.

But then the question was how does BCL-2 work? What sort of mechanism does it actually regulate? And so the rest of my career has been following molecule by molecule upwards from BCL-2.

Matt Smith:

And to that, maybe the cell death pretty much gave you a bigger problem.

Prof. David Vaux:

That’s right. So cell death has an interesting history. The first people that recognized that cell death was part of normal physiology were some histologists in Europe in the 1940s. Cell death was discovered and then forgotten probably a dozen times between then and now. Although cell death occurs to a million cells in our bodies every second, it’s a very efficient rapid process. A cell kills itself, takes about half an hour and then it’s swallowed up by neighboring cells and then there is no trace left.

That’s why people kept overlooking it because you could just take a normal tissue and look at the cells, you don’t see any cells that are killing themselves. Once the mechanism started to be understood and once there was this link between failure of cell death to causing cancer in humans, then suddenly it became a very interesting topic. 2.5% of all publications in the medical literature mention programmed cell death or apoptosis which are the technical names for cell suicide.

Matt Smith:

So how are you going about finding out what sort of things can affect cell death?

Prof. David Vaux:

One approach that we’ve taken is to look at viruses. It turns out that the mechanisms of cell death are highly conserved amongst the animals. So the same mechanisms that are involved in cell suicide in our bodies to a million cells every second, the same mechanisms are involved in destruction of caterpillar cells so that it can reform its tissues to produce a butterfly so you can see that same genes and the same types of proteins were involved in those processes.

So it’s highly conserved through evolution. Now cell death also occurs as part of normal physiology in plants, but it seems to use a different mechanism, but it raises the question, “When did cell death evolve?” We think that the cell death mechanisms might have evolved even in a single-cell organism. But they weren’t used in a single-cell organism as part of a program for development because if you only got one cell, there’s nothing really to develop. But they might have evolved as a defense against viral infection because all viruses need to take over a cell’s machinery in order for the virus to replicate. So good defense against the virus is for a cell to kill itself and then the virus can’t replicate. So cell suicide probably evolved as a defense against viruses and then later the same mechanisms were used for development, separating the fingers which in the embryo are webbed together.

But viruses can evolve very rapidly, and so viruses often carry cell death inhibitory genes. In fact, if you look at the genome of almost every virus, they carry cell death inhibitors and they use them to keep the cell alive while the cell makes more copies of the virus. So a good way to find more components of the cell death mechanism or more tools to understand that is by looking at the genome of viruses.

So it turns out some viruses carry copies of BCL-2, like adenovirus that can cause conjunctivitis. It carries BCL-2-like gene. Some of the herpes viruses carry BCL-2-like genes. So we started looking at some viral genomes and we started looking at some viruses that infect insect cells and these are called baculoviruses.

Now Lois Miller in the United States found that these baculoviruses and insect viruses carry some cell death inhibitory genes. So we started analyzing some of them and we found that when we took those insect virus genes and turn them on in human cells, in tissue culture, it stopped those cells from being able to kill themselves. So that led us to hypothesize, “Well, maybe there are some cellular mammalian IAP genes.” These genes called IAPs were inhibitors of apoptosis proteins.

So that led us to identify a whole family of IAP genes in mammalian cells and now it’s turned out that these IAPs regulate some of the signaling that goes from the surface of a cell down to the cell death machinery within the cell. So it’s provided another link in that pathway and these IAPs are themselves inhibited by some pro-cell death proteins and there is one that we identified and we called Diablo and another group in the United States identified and they called SMAC.

So now some pharmaceutical companies have made drugs that are known as SMAC Mimetrics or IAP antagonist compounds. There are three of them now in clinical trial for the treatment of cancer in humans. So we don’t yet know whether they worked or not because it’s just in phase I trial, but it illustrates how research on things is akin as insect viruses can lead to the better understanding of how human physiology and pathology works and that in turn can lead to development of new treatments or potential treatments for diseases such as cancer.

Matt Smith:

Yes. That’s really just putting viruses to good use.

Prof. David Vaux:

Yeah. That’s right. Taking clues from evolution and biology and using the tools of molecular biology and structural chemistry and so on to get a better understanding of what’s normal and then to apply that to a disease.

Matt Smith:

Prof. David Vaux. Thank you for your time.

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