Spontaneity Tissue-specific Mutation Helps Curing Inborn Immune Deficiency (BIOL 5104 blog 2)

This is a true story told by Dr. Liwu Li yesterday. It is really amazing so I would like to share this with you.

Even the topic I am using is so attractive. We know genomic equivalence, which means in one organism, each cell has the same sets of genes. Mutation may happen in single cell but should not be tissue-specific except in embryo stage. But how can tissue-specific mutation just happen in a 25 years old human being?  I can’t imagine this before knowing the following story, the answer to this question is cancer. Then, more and more people are curious in curing of inborn immune deficiency. It is a big problem in medicine and in biology as this kind of deficiency is determined by genes. But if we can find a way to repair the genes even in adult cells, it must be great improvement in medicine and biology. Here comes a possible way.

Once a day, a physician encountered a boy with a very strange disease. The boy’s skin is full of ulcer everywhere because all of his neutrophil (a kind of leukocyte) do not work. Of cause the boy is very easily to be sick. After study, it is just a single mutation in the end of chromosome 13 causes this symptom. So it is a kind of inborn immune deficiency. As I mentioned above, till now we have nothing to do to cure inborn immune deficiency. That physician did not give up, he explored the articles and find one single paper in 1960s reports one patient who has the almost the same symptom as the boy. But the results are the same, no way to cure that. However, very coincidently, the physician found that the patient described in that paper is the mother of this boy! Why the physician didn’t notice this at the beginning? Because the mother does not have the symptom and she even forgot she used to have. When she was 25, the symptom suddenly and spontaneity disappeared without any medicine or treatment! And that happened several years before she gave birth to this boy. By sequencing the mothers’ different tissue cells, the physician found that the mother does have the single mutation in different tissue cells except in neutrophil. This can explain that the mother doesn’t have the symptom but it can be inherited to her son. But why this happened? It is answered by a very simple experiment, observing the neutrophil’s chromosome by microscope: the whole part of the end of chromosome 13 which contains that SNP is missing.

Chromosome breakage causes the chromosome deletion. There are three possible results of chromosome breakage, first on is been repaired. There are repair mechanisms to relink our chromosome which happened every day in out body. But there is very little possibility that we fail to repair a broken chromosome or relink chromosome in a wrong way. Within this situation, most of such cells will encounter apoptosis, very little of them will become cancer cell because cancer gene is somehow be activated by chromosome breakage or falsely relinking. What’s more, our body has variety of mechanism to recognize the cancer cell and kill them before they develop. So, back to our story, the mother’s neutrophil is the results of such an extremely rare event, suffer chromosome breakage but still alive, even functions normally. First, the region of chromosome 13 that the neutrophil lost contains many genes including the single mutation causing that syndrome, but luckily, none of them are useful to neutrophil. Second, if only one neutrophil has such broken chromosome, it will not make any difference, but it is impossible that multi neutrophils have the same broken chromosome at the same time. What’s miraculously is this chromosome breakage also triggers the cancerization of that single neutrophil. And furthermore, it didn’t develop into the kind of invasive spreading cancer but a little bit aggressive that killed other neutrophils and become dominant. As the result, most of the neutrophils are daughter cells of that single neutrophil which has the normal immune function.

That’s all about the story that I heard, but it will never come an end. It may open a whole new gate for medicine and biology. If we can find the ways to change different tissue’s single cell into a kind of cancer cell which is aggressive but not invasive spreading and still functions normally like the neutrophil in the above story, it may be a wonderful way to cure inborn genetic deficiency. On the other hand, this extremely rare event (chromosome breakage in that specific region in that specific cell) happened in that mother. Is this really a random event? By suspecting this question, we may discover other great things.

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