Monday, July 14, 2008

Death and multiplication

You may well ask why I have posted so many technical articles recently. Anyone who attempted to come to terms with yesterday's offering may well have given up half way (if they got that far) with the question, "Why do I need to know this?" I must confess that that has been exactly my reaction over the last few years, but the extra time that retirement brings has meant that I can read more widely.

When I was at University there was no such subject as molecular biology. DNA was never mentioned and even biochemistry was no more complicated than the measurement of urea and glucose. When I was a postgraduate student genetics meant learning about inborn errors of metabolism such as sickle cell disease and G-6PD deficiency, and although the thalassemias opened our eyes to the complexity of genetic disease, we had our hands full with extracellular biochemical pathways, and the inner workings of the cell were a black box.

Later, I began to hear about processes that perplexed me. Words like apoptosis and caspase were opaque to me, as were promoters and enhancers, introns and extrons, and especially words like myristoylation. Then there were the acronyms. Unless you know their origin (which are usually hard to find) you are like a juggler with too many balls in the air. When you read a difficult passage of prose and you come upon a word you have never seen before you can often guess its meaning from the context. I had this problem when I read the Patrick O'Brien books of the Master and Commander series. Technical terms from eighteenth century sailing ships kept cropping up. If you can't guess them then you have to hold them in the air in the hope that all will be explained. Eventually you have so many balls in the air that you start dropping them.

(As an aside let me tell you the story of the Jnk gene - pronounced junk. You'd think it was something to do with junk DNA, which couldn't be further from the truth. It stands for Jun kinase. And Jun is nothing to do with either the month or the girl, it comes from ju-nana, the Japanese for the number 17 because it was isolated from avian sarcoma virus 17. Jun is often associated with Fos which itself is nothing to do with the Fosse Way, but comes from the FJB murine osteosarcoma virus. FJB? These were the people who isolated the virus in 1966, Finkel, Biskis and Jinkins.)

So without going back to the previous article, can I explain src family kinases for those who can't manage the technology?

All cells in the body have things to do. For many their chief function is to manufacture something. For example the chief function of a plasma cell is to make antibody. But most cells have two common functions : to reproduce themselves and to die. Of course, some cells have reached the end of their reproductive life and death is all they have to look forward to. Reproduction and death are very specific and non-random procedures, and they are done properly and in order according to protocol. In the growing embryo, death and multiplication are pre-programmed and take place in a specific order, but in the adult death and multiplication result from external stimuli in the context of the tissue that they live in.

Cells have receptors on their surface to receive these external stimuli. For example, breast cells have estrogen receptors, thyroid cells have receptors for thyroid stimulating hormone etc. White blood cells have very many receptors and alongside the receptors they have co-receptors that modify the way the receptor responds to a stimulus. For T-lymphocytes the T-cell receptor (TCR) only responds to a particular foreign stimulation - it will respond to measles but not to mumps, for example. It is therefore called a cognate response because it seems to know when it should respond and when it should not. For B-cells it is the same, only we know that the B-cell receptor (BCR) is actually the antibody that it has been pre-programmed to make.

The decision on death or multiplication is made in the nucleus of the cell. It involves switching on certain genes and switching off others. The mechanism is in the hands of proteins called Transcription Factors. So how does a message get from the cell surface receptor to the nucleus? Obviously there has to be a system of relays which pass the message along. These signaling molecules pass their signal to the next relay in the form of a parcel of phosphate - often attached to an amino acid called tyrosine, which is part of their protein structure.

Of course, it is much more complex than that with stimulatory and inhibitory processes kept in balance so that all changes are smoothly modulated. The relay pathways are not straight lines, but have branch lines that affect the final outcome. But I am sure you get the gist.

In cancer, these pathways are disorganized. Death and multiplication are both affected. Programmed cell death (that's what apoptosis means) is usually inhibited and multiplication is exaggerated. It is quite obvious that cells must sometimes multiply more quickly than normal - during an infection more white cells must be produced to fight it, but when the emergency is over the number of white cells must return to former levels. Therefore these things must come with an 'on' and 'off' switch. Very often in cancer the switch is jammed in the 'on' position.

If we are to develop truly targeted treatment for cancers we must understand what the molecular mistake was. Glivec (Gleevec) has been successful because the disease, CML, has a relatively simple molecular mistake. The multiplication enzyme known as ABL (short for Ableson) is jammed in the 'on' position. All such enzymes need a power supply to keep running and what Glivec does is to cover up the socket where the energy supply plugs in. This puts ABL out of action and the result is remission.


Anonymous said...

I, for one, really like the medical postings. The religious ones are interesting, but your perspective on CLL can't be found anywhere else.

Ravonda said...

I enjoyed dropping by for a visit today. I have a google alert set up for "osteosarcoma" because this is the cancer my daughter has. I came because of your mention of it, but lingered a while because I am a Christian and you had something worthwhile to read.