Science: Unconventional wisdom

UNDER THE MICROSCOPE: CANCER MIGHT NOT BE CLONAL

Dear Dolly, I think you are now old enough to start learning about clones because it is a word that will bedevil you all your life. It is a term we cell biologists often use in order to describe the relationships between cells. Let me give you an analogy that may amuse you. Think of a mother animal at the bottom of a steep mountain, and let us pretend that she is a mother lemming. This mother lemming gives birth to a daughter lemming who begins to climb the mountain. On the way up, the daughter gives rise to another lemming and as they too continue to climb up the mountain they too reproduce and make some more lemmings and continue to do so until they are about half way up the mountain when they stop reproducing; but continue to climb to the very top. And then when they get there they fall off and die. All those lemmings are part of a clone as they are all descendants of that mother lemming at the base. She is, as it were, the stem for all those lemmings. She is special and remains there all her life ensuring that her daughter lemmings and their daughters are always climbing up the mountain.

Of course, Dolly, that is just a story but if you were able to look at the cells lining of my intestine you will find a very similar situation. The surface of the intestine is highly folded and there are long extensions which absorb the food. At the base of these extensions - called villi - there are cells which are the equivalent of the mother lemming, and are known as stem cells. They divide rather rarely but their daughter cells divide as they ascend the villi, then die and fall off. This is presumably a mechanism to deal with the constant wear and tear that the lining of the gut is exposed to.

But there is a negative side to such a protective mechanism, for the stem cells and their offspring are cells that divide throughout the life of the person. Nerve and muscle cells, by contrast, never divide. Cell multiplication requires the call both to grow so that all its components are doubled up, and then to divide so that the daughters each receive the same full set of components. These are complex processes and so there is a real danger that things will go wrong, mistakes can be made, and when this occurs in multiplying cells it can give rise to cancer. This is why most cancers arise in tissues that contain dividing stem cells and their offspring. Thus most cancers are found in the lining of the intestine, the skin, where cells are continually being lost and replaced, and the blood where there is a similar process - red blood cells, for example, only live for about 40 days and so need constant replacement.

The conventional wisdom about the origin of cancer is that it comes from just a single cell having a change in its genes so that instead of climbing the mountain and dying it multiplies out of control and spreads to foreign sites. This means that every cancer is a clone, all the cancerous cells are derived from that single cell which contained the fatal errors. In the case of the intestine it is thought that it is the stem cell which usually goes wrong and is the source of the clone. However, recent studies have shown that this might not always be true. Under special circumstances it is possible to find that the intestine is a mixture of two cells types which differ only in a trivial way but makes them distinguishable from each other. The unexpected finding was that cancer that arose in such a situation was made up of both types of cells showing that it originated from more than one cell. The reason for this is unknown and raises important questions about how cancerous cells develop. Do the cancerous cells need to cooperate to form a tumour?

So cancer may not be clonal after all. But, Dolly, do remember that there are other famous clones since we are, ourselves, essentially clones - every cell in our body being the descendants of the fertilized egg!