A blog about science because it's a wonderful thing. No real theme, just topics I chose to write about because I understand them (biological science, mostly to do with viruses). I am a PhD student in Cell and Molecular biology, studying immune defence to viral entry, at University College London (credentials). Enjoy...
Wednesday, 13 June 2012
Caspase: the not so friendly protein
It’s somewhat of an antithesis to say that death is
essential for life, however in multicellular organisms, such as humans, without
cells dying we would not live. The topic of this week’s blog is therefore a fundamental
phenomenon of all cells in our body termed apoptosis, or programmed cell death.
As the name implies, this form of cell death is highly controlled and
essentially runs a program to cause the death of the cell. Apoptosis is
controlled by a set of proteins called caspases which drive the necessary
changes to kill the cell.
So why do cells need to die? There are a lot of answers to
that question but I will only look at a few of these. Firstly, right back when
we are a foetus we all start with webbed hands and toes (see the image).
However, I assume most people no longer have such webbing, a fact which all
comes down to death of the excess cells between the digits. Another example of
this sculpting process can be seen when a tadpole matures to a frog (the
tail isn’t chopped off by a small frog knife).
Human embryo hand at 8 weeks
Two further roles for apoptosis can be seen during
infection. Viruses enter cells and use them to produce many new viruses,
causing damage to the host. One of the front line defences against this is to
simply kill the infected cell, which blocks replication of the virus. Also when
we are infected with any pathogen an immune response is produced. This response
is controlled by white blood cells, our army against the invading infectious organism.
When an organism enters the number of white blood cells rapidly increases, in a
sense, the army begins conscription. When the infecting organism has been
removed from the body all these excess cells must be removed otherwise they
could cause autoimmune disease (where they attack healthy tissue causing
disease), or could continue growing in number, causing a cancer. This removal
all comes down to cell death.
The final example for the importance of apoptosis I would
like to look at is in development of the brain. Our brains are initially made with
a huge excess of neurones. Interesting these cells (like many others) are
naturally programed to die; death is the default setting. The cells in the
brain only survive if they are able to make contacts to other cells (forming
synapses). The cells that connect in the brain survive and produce the brain of
the foetus; those that make no contacts undergo their default setting and die,
so as not to clog up the brain with excess, useless neurones. Around 50% of the
initially produced neurones will die because of not making any contacts. Apoptosis
is therefore an essential function for life, without it we would not progress
beyond being an embryo.
So now the question to ask is what causes cells to die. As I
mentioned, the key players of cell death are proteins called caspases. Caspases
are expressed in all cells as zymogens, a fancy word for an inactive enzyme.
These zymogens sit in the cell waiting for any time there is a trigger to
activate them. This can be thought of almost like a light switch, everything is
there waiting to be turned on, but it needs you to press the switch to get
light. In the cell there are two main pathways that lead to activation of the
caspases; intrinsic and extrinsic pathways. Intrinsic signalling relies on proteins
in the cell which form pores in the mitochondria (the molecular machine that
produces energy in our cells). These pores cause the release of two proteins,
called cytochrome C and Apaf1, which together bind a certain caspase (caspase-9)
and cause its activation in the ‘apoptosome.’ The extrinsic pathway relies on a
receptor on the surface of the cell binding a signal (this is the case in the
immune response for killing infected cells.) When the receptor engages with its
target protein a platform is set up inside the cell called DISC (death inducing
signalling complex) which binds capsase-8 and activates it. While both pathways
activate different caspases the effect is the same; RIP cell.
Apoptotic cell blebs being engulfed by a macrophage
With the activation of caspases our poor cell is terminal.
Many changes occur to the cell and these are all controlled by the activity of
caspases. Firstly the cell begins to shrink as all the proteins that keep a
cell at its usual size are broken up. Over time the DNA inside the cell is
chopped up into tiny fragments, rendering the cell useless. Eventually parts of
the cell start breaking off in small units called blebs, until at the end a big
macrophage (an immune cell) comes along and eats up the cell. This may sound
like a pretty nasty way to go, shrinking down, having the DNA chopped up and
then being eaten by a giant, but this process protects the rest of the organism
from damage. Other forms of cell death often involve the cell bursting which
causes inflammation in the surrounding area and therefore more extensive
damage. Apoptosis, on the other hand, is completely silent therefore providing
the most effective and safest way to kill a cell.
It fascinates me how essential cell death is for life.
Without death we could not be born; it’s that fundamental. We continue to need
cell death right up to our own death as it can protect from cancer, aid in
clearance of infection and may help to stop autoimmunity developing. However
too much death is obviously not a good thing either and is seen in many
neurological disorders, so it’s a fine balancing act between the good and the
bad of cell death. It’s also interesting to think of cell death in an
evolutionary sense. When life began it was only as a single, isolated cell
whose only purpose was to survive. As life became more complex and organisms made
of multiple cells emerged, the ability to kill off a few cells to protect the
organism as a whole became a huge advantage. Perhaps the evolution of this
self-sacrifice was an essential step in the development of complex life itself…