Allocution - Prix A.R.C.

J. Lejeune

RENO december 1985


Sommaire

Mr President, and dear members of the Association for retarded Citizens of the United States.

Recieving your kind invitation to Reno was a great honour and I felt in the same time a great delight and a deep sorrow: all my teaching duties are accumulated in October, November and December! and Who in the world could modify an University's calendar!

I profoundly regret not to be able to join this meeting but my hope is you will nevertheless forgive Me, considering that I am pleading both "non-guilty" ... and sincerly repentant.

In bestowing upon me this Research award, the Association for Retarded Citizens of United States has distinguished a work still to be completed. Sure enough it is now well establised that an extra chromosome 21 is the cause of Down's Syndrome. But how this super numeracy piece of genetic information produces its deleterious effect ;

- how the intellectual damage is resulting from it,

- how it could possibly be compensated or repaired,

All this remains to be discovered.

Hence, instead of an historical review, I'll take the liberty of presenting you briefly the state of affairs, and discussing the various ways open to research.

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Types and counter-types

Normally, at the moment of conception, every child recieves two exemplars of each chromosomes : one from father, one from mother. If by misfortune one of the reproductive cells carries two, elements, the child becomes trisomic that is he has three exemplars of chromosome 21.

Sometimes the contrary occurs, a piece of chromosome is lacking and the child is monosomic, having received only one exemplar of this segment.

If we compare the two conditions, a stricking opposition appears the excess modify the morphology in one way and the deficit on the contrary way.

For example, trisomy 21 produces small ears with a small nose and partial monosomy 21 induces large ears with a protruding nose.

This opposition in "Type and Counter-type" is observed for all the chromosomal aberrations for which these reciprocal syndromes are known. But not matter the chromosome involved, be it the 21, the 18, the 13 or the 5 or any other, then it comes to intelligence both the excess or the deficit of genetic material invariably produce the same deleterious effet : mental deficiency.

In order of resolving this paradoxe, we must remember that the genes, carried by the chromosomes, dictate the production of enzymes. Enzymes are the machine - tools of the cell, manufacturing all the biochemical products. Hence the more genes there are, the more enzymes are produced and the fastest the chemical stuff is produced or destroyed.

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The symphony of intelligence

The message of life can be compared to a symphony : each musician (the genes) reads its score and follows the tempo of the conductor.

During a solo, a too-quick musician (in case of trisomy) could transform an "andante" in a "prestissimo" : the ears will be too small and the fingers too short. Conversly, a slow musician (in case of monosomy) could change an "allegretto" in a "largo" : the ears will be chiseled and the fingers too slender. In both cases, because the musician played a solo, he modified a trait but did not spoiled the whole symphony.

On the contrary, when the full orchestra is concerting, all the not musician playing in a "tutti", it does not matter wether the faulty musician accelerates or slows down ; the result will be cacophonic, even if he reads correctly his music!

Detecting the discording musician is not an easy task especially when a whole chromosome is involved like in Down's Syndrome. In simple genic diseases, like in phenylketonuria for example, only one biochemical reaction is blocked and the failure is obvious... once discovered. But there may be some thousand genes in chromosome 21.

Surely, most of them do not produce harm when in triplicate, because if each of them was discording, the trisomic children would not survive at at all. Thus only few of the accelerated reactions are dangerous. But how will we discover the culprits among so many innocents!

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Chromosomal regulation

This detective story could be avoided if we knew how to silence a peculiar chromosome without disturbing the others. If the extra musician was turned off, the symphony would be restored.

Let us suppose a competent repair-man has recieved from the factory a four cylinder engine equipped by mistake with flue spark-plugs. He would certainly notice that the engine does not run smoothly. An expert would not discard thos motor. He would cleverly disconnect the extra plug and thus bring the rythm to normal.

Alas, we are not yet as skilled than this car repair man! But Nature is that shrewd. She konws how to silence one of the X chromosomes in feminine cells, so that the woman with her two X chromosomes is not so much superior to the man who has only one X and a tiny Y!

We still ignore how this turning off is achieved. Il we could master that trick, and if we could apply it to the extra chromosome 21, we could redress the destiny of Down's Syndrome affected children, even without knowing what kind of biochemical reaction was modified by the discording musician!

Pending such a tour de force, (and nobody knows wether it would at all be feasible some day) we can try to decipher the genic content of chromosome 21.

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Genes on the 21

The painfull task of unravelling one by one the genes of chromosome 21 is less brilliant indeed, but it has the great advantage of being already on the way. Two methods are available :

- the molecular biologists split the long ribbon of the DNA contained in chromosome 21 and, letter by letter, decipher the message encoded in each piece.

- on the other hand the biochemists carefully analyses all the chemical reactions they can, in order to see if some of them are running faster in trisomic 21 cells.

These two approachs complement each other and engender a healtly scientific competition between the research teams.

For the moment six genes are known and I apologize for being too technical about it : chemical language is very simple indeed, with the slight difficulty that it cannot be translated in every days words!

One, the superoxyde dismutase (S.O.D.I), plays a special role in the metabolism of oxygen. So to speak, it regulates the carburation. Its over activity possibly deteriorates some cell constituants, inducing the too rapid ageing of Down's Syndrome patients. They also become more frequently deficients and some of them are affected by a redoutable complication looking very much like the ALZHEIMER disease.

- Another, the phosphofructokinase controles the sugar metabolism and part of the fatty acids production. Trisomics 21 are prone to diabetes and are often overweighted.

- Two twin-genes, the glicineamide phosphoribosyl synthase and the aminoimidazole phosphoribosyl synthase deal with the production of purines, the building blocks of DNA. Trisomics spill over these purines as demonstrated by an increased excretion of uric acid.

- The gene responsible of the protein reactive to interferon works also too fast. The trisomics are prone to various infections.

- The last one, discovered last year, is the cystathionine B synthase which transform homocysteine into cystathionine, a very important compound. A rabbit has less cystathionine in its brain than a dog ; a chimpanzee has mare than a dog and a man, more than a chimpanzee ...

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The monocarbon hypothesis

To suggest some strategy for efficiently continuing the attack, we need a theoretical framework to put in order these miscellaneous informations and to conduct the next assaults.

Could it be that a peculiar chemical mechanism would be the most frequently affected in mental retardation? Few years ago I proposed that the metabolism of monocarbons could be this sensitive target.

In order to build the eleven thousand millions of neurons in our brain, to insulate its enormous wiring (as long as from Paris to Reno) and to chisel the security keys who open and close the eleven millions of millions of connections between our neurons the brain makes an enormous consumption of monocarbons. These bits of molecules, containing only one atom of carbon (hence their name) are the smallest building stone of our nervous system, but the most used one.

Thus if the supply of monocarbons was insufficient, if its transportation by folic acid and B12 vitamine was not efficient, if its utilisation by transmethylases was not appropriate, a severe disturbance of the functionning of the brain would ensue. All that we know about the mentally deleterious effect of these impairements is in accordance with this oversimplified hypothesis.

If some very precious stuff was burned too fast by trisomic 21 children, this wastage could possibly deplete their organism of a very necessary compound.

When over-producing purines, as previously mentioned, trisomic 21 cells waste quite a lot of those precious monocarbons.

In this respect the newly discovered acceleration of the cysthionine-▀-synthase could even be of a greater interest.

In a different type of mental retardation, the homocystinuria, this very reaction is totally blocked ; exactly the contrary of the acceleration in trisomy 21. Curiously homocystinuric children are tall, slender, with long tappered fingers, just the opposite of the short stature and the short fingers of trisomics 21. Even the homocystinurics have extra creases on their fingers in contrast to the lack of some flexion creases in trisomy 21.

The type and counter-type me started with in our discussion is very obvious here.

And this comparison is also in accordance with the monocarbon's hypothesis. Homocyste´ne, if not transformed into cystathionine, recieves a monacarbon carried by folic acid and B12 and becomes later S-adenosyl methionine ; this is the transport form of monocarbons. The next step is the construction of neurons, of insulating substances and of security keys of the nervous connections! Taken together the wastage of purine and the excessive destruction of homocysteine could produce a borderline but chronic shortage of monocarbons in trisomy 21.

On the contrary, the accumulation of homocysteine (in the blokade disease) produce S-adenosyl-homocysteine which entirely blocks the transmethylase system ; thus the blokade is just as deleterious as the acceleration.

It must be very precisely stressed that this general model is for the moment strictly speculative. Even if the reasoning was sound, it would remain to be seen wether the correction of such a trouble, if at all possible, could alleviate the mental deficiency.

Mr. President and dear friends, please forgive me for this too technical discussion. Its only purpose was to show you that research is on the way and that me must make every endeavour to pursue it.

Sure enough nobody knows the length of the road to be covered before reaching the achievement we are all longing for, dedicated parents, skillful teachers and research workers. But one thing is certain, thanks to this cooperation and to the help of valuable associations like yours, we will indefatigably try to render to the children injured in their intelligence, this marvelous glaring who is the mark of the spirit.