Genetics and mental welfare

Jérôme Lejeune

C.R. Congrès de Moscou, août 1978. In : Well-being of mankind and genetics. Vol. I, 102-109


Beside the pure intellectual curiosity, which is admiration of the marvels of the world, welfare of mankind is the final goal of any science.

So much will be exposed during this Congress about the new achievements of Genetics, from basic molecular mechanisms to practical application to human health and wealth, that I want to focuse, not on the general human welfare, but more precisely on the human mental welfare.

Mental welfare requires absolutely two conditions : the liberty of using the power of thinking and the very possession of this power.

The history of Genetics can show us how those two conditions can and must be realised.

As for any science the liberty of using all the powers of our mind, without any bias or ideological restriction is, so to speak, "consubstantial" to genetic knowledge.

The blind alley to which LYSSENKOISM was leading genetics, is an experimental demonstration of such a necessity.

Years ago, when I first came in this country, I had the priviledge of being an eye-wittness of this phenomenon. It was short after the observation of the chromosomal aberrations which can afflict human beings, and I remember an anecdotic but very revelating event.

In front of some pictures of human chromosomes, showing trisomy 21 of Down's Syndrome, Haplo-X condition of Turner, and soon, a very vivid discussion arose, in the exhibition, between scientists.

Some of them declared that such things were forgery because Mr LYSSENKO had prescribed genes and chromosomes were pure fancy, not fitting his theory. Hence they should not exist at all.

Others were of the opinion that eventually nature knew better than theoreticians and reckognized that if theories were not fitting the facts, it was the theories which should be rejected, not the facts.

This disputation came to a real turmoil and if I recall it today it is for the new generation of scientists who even do not know about what happened in those years long past !

They have to realize not "in abstracto" but in historical context that the laws of the creation are our only teacher; not the laws which are, temporally, accepted or imposed, according a theory.

Developing this subject of the prerequisite liberty of the geneticist, would nowadays be considered, either as a common place argument, or as a rather subversive allusion, depending upon what is politically implied by the term of liberty.

Without trying a difficult navigation between these two pitfalls, let us look at the other side which is the actual possession of the power of thinking.

Amongst the deleterious phenotypic effects resulting from genetic disasters, from point mutation to chromosomal mistakes, one is the most dramatic, the debility of intelligence. This is the most typically human disease because only humans can suffer of it and also the most inhumane, for it prevents the patients of sharing their full part of mankind's patrimony, the blossoming of the thought.

To try to understand what is hampering the intelligence of genetically affected people, we can possibly first ask ourselves whether the intellect is really imprinted in this accretion of matter, we call the human body.

A very typical example of the power of the intellect is the field of geometry, the purest or at least the most abstract of all sciences.

History again can be of some help here.

It is generally believed that geometry was invented by old Egyptians and such a statement seems very plausible.

Before the Asswan reservoir was built, there was every year a great flood of the Nile. After the withdrowal of the waters the land was very leveled off indeed. Hence what more natural than to sow few pyramids on that flat plane !

Although I do not object to the ingeniosity of ancient Egyptians as a geneticist, I do not guess that geometric knowledge really started that way.

Let me propose you another origin, which is perfectly undemonstrable, but as remarked a french philosopher: "the most true stories are not always those which have happened".

As everybody knows lovers spend long hours (too short nevertheless) looking at each other eyes. This is so true that quite all human languages have the same definition of the circular opening of the iris, this dark little window though which we observe the world. In French as in English they call it "la pupille" "the pupilla", which means in Latin the little girl. Spanish would say " la nina del ojo". Greeks would call it "chorea" ; Iranians : "Mardomak" ; Arabians "Insan el Ein" ; Vietnamese : "Ngu oï" and Japanese "Hito me".

The reason of this universality is obvious. When you look very close to the eye of your beloved you see your own image reflected by the convex mirror of her cornea and this tiny puppet is the most luminous against the dark back-ground of the iris opening.

I would be inclined to suppose that women discovered first this interesting optical property ; hence most of languages using the term of "little girl" (and not "little boy").

The postulate we have to make now is that one day a would-be geometer fall in love (such things can happen, even to, mathematically minded people) and he discovered geometry.

The cornea is a segment of sphere, intersecting another sphere of greater radius, the ocular globe.

Such intersection is thus a circle. On this circle is anchored the radial muscle of the iris (the dilator pupillae) and its fibers are stretched by the constriction of the orbicular muscle which delineate the pupilla itself.

Hence, under the sun of Egypt, the cholinergic orbicular muscle was quite closing the pupilla so that the inventor of geometry, observed experimentally the only perfect plane existing in this world, a surface anchored on a circle and defining the shortest possible distance between any two points of its fibers.

Euclide in a glimpse of love, how it would be comforting for school bays to learn that! (A friend of mine recently told me that modern geometers do define the plane from the tensorial calculus !).

We can go deeper, but it took few millenaries before DESCARTES achieved it. If you gently press your closed lids in a rather dark room, you will suddenly see a kind of chessboard made of tiny cells alternatingly dark purple and shiny golded, defining exactly the so-called cartesian coodinates, imprinted in the network of the retina long before any man was there to notice them.

DESCARTES discovered it because he was doubting and doubt prompt you to rub your lids to see if you have well seen. Hence the analytical geometry that everybody uses intuitively and only algebrists are talking about.

We know still mare nowaday. Neurology has lead us farther on the visual pathways. From the little window through which light is entering, to the obscure center which sees (in the calcarine region of the posterior part of the brain), we can follow all the development of modern mathematics.

Projections, bijections, rings and ideals, fibrous spaces, matrices and lattices, all the progeny of the ensemble theories were genetically there, only awaiting topologists took notice of them.

And this mirror of the soul, as the eye is generally called, reveals immediately to a human geneticist if the child he examines is intellectually unfitted or mentally gifted.

The look of a child affected by trisomy 21, is typically atonic and does not have this sparkling light that a normal child would show.

Here we can take advantage of the fact that the radial muscle of the iris is adrenergic and the orbicular muscle, cholinergic. By installating in the eye various drugs which can either stimulate or paralyse the adrenergic or the cholinergic mechanism, the answer of the muscles can be observed by the opening or the closing of the pupilla.

This very simple clinical investigation showed us that trisomic 21 children are hypocholinergic and, eventually, this minute symptom will reveal itself as very important for understanding the chemical basis of the disorder.

But, before discussing this particular subject we should better consider more generally the substratum of intelligence and figure out what difficulties could impair its functioning.

Two ways are open here, one is to enumerate the impressive array of genetic diseases known to produce mental deficiency; but how to give some sensible order to such a lengthy and frightening listing?

The other way, is to look for an equivalent of the human mind or, more modestly, to analyse the functioning of the machines which can simulates some of the intellectual fonctions. The calculating machines are an obvious model. Although they vary greatly in their particular construction all of them respond to some general characteristics, imposed by the performance they must achieve.

From the "machine arithmétique" of Pascal using only the geometric invariance of gears and barrs, to the giant electronic computers, (without forgetting Jet deflexion systems, laser driven informatic devices, or purely magnetic bubles running in a proper circuity), all of these engines satisfy to three constraints.

a) a logical network entirely preprinted.

b) a clean transmission of signals from place to place, with no diffusion and no short-circuits.

c) a two-way choice at each intersection of the network. (As Alfred de Musset said " il faut qu'une porte soit ouverte ou fermée" "A door must be open or shut". This is the very root of the binary logic, represented by the "gates" of electronic devices).

These three conditions are stringent because logic is anti-randomness it sole function is to forget about the fortuitous to keep only the deducible.

Hence the path followed must be meaningful in itself, and all the turns made inside it, must be "yes or no" and never "may be".

A calculating machine is not allowed any variance in its running, in accordance with the fundamental law of informatics : the amount of information carried is the inverse of the variance : I = 1/?

But eve comparison with the biggest machine actually bundled, the brain of an average human geneticist is at a reassuring advantage.

First its complexity is overhelming.

With some eleven thousand of millions of neurons it outnumbers largely any forseable computer. Every neuron itself is already a mini-computer, far each junction it makes with other cells is the equivalent of one transistor. As each neurone can make and recieve some thousands to ten thousands of these junctions, the number of synapses, the basic components of our machine, must amount to some 10 to the power 14; an astronomical chiffre!

The wiring , relating these components between theme is not known in details, but its total length can be roughly estimated. Possibly something like, from here to the moan and back!

And the most bewildering of all is that the precise instructions necessary and sufficient to build this fantastic machine, is properly imprinted in the some eleven thousand millions of bits of information of the DNA enclosed in the first human cell, the fertilized zygote! Let him live, he will think: that the human destiny.

Here were touch the fundamental difference between computers and mind Sure enough computers have been produced by the intelligent thought of their maker: machines are truly speaking disenchanted intelligence; it's why their power is sometimes frightening.

Men in the contrary are incarnation of intelligence. It's why they are so precious.

Another difference is an the way matter and energy are mastered by the synapses of the brain. These tiny bodies, apply the greatest paradox of quantified physics, they separate the particule of matter exactly as the ingenious devil of Maxwell was supposed to it.

Starting with a mixture of particules running at different speeds, the Maxwellian devil was opening or shutting his minuscule gate, letting bight velocity ones go one way, and closing the door to the slow ones. So he could separate in two vessels, one hot, one cold, what was at the beginning a statistical mixture. He was ordering the disorder and running against the entropy.

Synapses just do that. When a molecule of mediator, say acetylcholine or adrenaline is released from the vesicules situated at the end of a neurone, the axonal button, they change suddenly the properties of the receptor, of the next cell. Abruptly this membrane can engulf, one by one, ions of a given type, and thus work against entropy. And there is no wonder to find this equivalent of the Maxwell devil at the very heart of the brain machinery. If really logic is founded on the exclusion of randomnes its substratum must use the only physical paradox which allow to do so.

Possibly, the failures we can observe in the calculating machine, could lead us to analyse the genetic conditions which impair human thought.

All these failures can be put under thee headings: destruction or mistakes of the network itself, abnormalities of the insulating material and disfunctioning of the components.

Genetical errors leading to malfabrication of our precious network are, alas, too frequent, ranging from total anencephaly preventing the development of the whole brain, to partial misplacement of tissue, through specific aplasia like arrhinencephaly of trisomy 13 or agenesia of corpus callosum of trisomy 18.

Also the hydraulic pressure of cephalo-rachidian fluid can laminate the brain in hydrocephalia.

Abnormalities of the insulating substances also occur. In most of them the cell can manufacture the substances (because a complete lack of them would be incompatible with the building of the brain), but cannot dispose of the surpluses and accumulate them to the point of being killed by this excess.

In Tay-Sachs disease for example, the lack of ß-hexoseaminidase lead to an accumulation of cerebroside substance and progressively the neurones die. Hence the tragic and progressive destruction of the brain of children born apparently healtly, although genetically and microscopically abready affected.

Nieman Pick disease, Gaucher's disease are terrible example of these disorders.

Even if the network is correct and the insulating system properly deve lopped, genetic mistakes can prevent the function. Generally speaking, one get the feeling that the machine is running but cannot develop its full power. Exactly like a motor to which the fuel is not provided in correct amount.

And the speed with which information can move inside our brain matters greatly. As every body can experience by himself we have to think at a proper path: try to speed up a reasoning and all the arguments will stumble on each other. More disappointingly we cannot brake either.

If we slow down too much the path of our reasoning, another idea will cross over our consciousness and we will loose the thread of our thought.

Temperature also is critical, below 30 degree, it's a comalike state above 40 degree, delirium appears.

In feeble mindness with no gross brain lesion, it is probably the speed which is the limiting factor. Being unable to handle every duty at the same time, feeble minded people, apparently shut same network and close some circuitries. They let their mouth open and their tongue prodruding because they cannot control every thing at once. Even a normal person would do so if all his attention is directed to a very demanding task or if he is admiring some object of beauty.

Also in feeble mindness the slowness of the elocution and the viscosity of the ideation are typical symptomes.

One would believe that either the brain does not dispose of enough energy or that some toxic is impairing its ignition process.

Among the most common toxic and among the most dateable indeed, Vodka is a perfect example. After the euphoric period, related to the shut down of some self-control circuitries, comes a progressive diminution of the brain activity.

Even the most alert molecular geneticist could not decipher a simple code after some glasses of it; The amount depending partly aPon personnel of genetical endowment, and partly upon proper training. Hopefully the recovery is plainly possible, at variance with genetic impairment.

Rather intriguing relationships are obvious between feeble-mindness and psychotic disturbance. As wisely stated by Chesterton "a fool is a man who has lost everything but the reason". Contrarily a feeble minded has lost nothing, but abstractive power. Although the field of psychiatry is in complete remolding, it seems already sure that many psychiatric disorders depends just as well, upon genetic factors.

But what about the motor ? the engine which deliver the energy to make the chimical mediators immediately avaible in the right place, in the right time, so that synapses can transmit an recieve the signals?

Here again the complexity is bewildering and to get an impression of it I tried to figure out a "pascalian machine" which could roughly simulate the intricacies of the chemical pathways.

In this artistic view (if I can say so), only the pathways well established enough to be found in current text books have been drawn; most of them uncompletely.

This is to say that the true machinery is much more sophisticated than this primitive over-simplification.

Nevertheless the analogy can be of some heuristic use. As BERGSON once stated "we can really comprehend a thing only if we can propose a mechanical model of it".

Just to fix the ideas, the energy is entering at button left bar glucose, galactose and fructose and is either stored in glycogen or used via the glycolytic pathway toward :

1) the krebs cycle, the A.T.P. producing dynamo,

2) the lipid production

3) the insulating substances

4) the purine synthesis via the hexane monophosphate shunt

5) the production of chemical mediators

6) the regulation process of their fabrication

To give an impression of the precision of the regulating process cystathionine, situated dust in the middle, is a curious molecule, known to have a taxonomic al significance.

Its amount in the brain is related to the place of the organism on the ladder of evolution.

A dog has much more than a frog, a monkey more than a dog and a man much more than any animal.

Over such a scheme, we can superimpose the genetic blockages known to provoke mental deficiency.

As expected by the analogy with computers, we discover that failures do happens in parts of the machinery which are normally achieving the three perequisites we stated at the beginning.

These dots do cluster in specific regions. On. left are the abnormality of insulating substances and on right the loss by mucopoly-saccharidose of stuffs used also by the regulatory process. On top left are mistakes close to the pro-duction of chemical mediators and in the middle various disturbancies impairing the regulator.

Now medicine has to handle the challenge; how can we improve this terrible situation, how can we alleviate this heavy burden of mental retardation affecting some 2 to 5 percent of the children at birth?

Here two ways are open already.

One is the social help and the admirable parental dedication which achieve every day repeated miracles.

Special teaching, unlimited love and full respect can help immensely de sinherited children, the poorest of the poorest: for millenary humanity has more or less striven in this higher direction.

Recently the progress of genetic technology has shifted in another direction.

Some biochemical errors can be detected early, eventually in utero.

Also chromosomal catastrophies can be observed by analysis of the foetal cells floating in the amniotic fluid.

A generalized tendency has been to propose systematic screening and early elimination of the suffering babies. Selective abortion is actually advertised as a "therapy" or a "management" of these diseases.

Selective destruction is a despair reaction. It is a kind of sophisticated racism, based on molecular or chromosomal discrimination.

But the dilemma, keep them or kill them, does not sum up the real situation.

Medicine is the third way. It is the way of the future of mental welfare.

In very limited cases, the victory has already been won, not against the patient, but against the disease.

Phenylketonuria, galactosemia, vitamine B6 dependant homocystinuria, to take few examples, can be properly handled and the children protected against:.mental deficiency.

Who could believe that during the coming years no new progress will be achieved?

If the scientific community was realizing the enormity of the task, the path of the advances could accelerate tremendously.

I do not believe personally about building a superhumanity someday by some genetic engineering trick. To devise a man, wiser than we are, we should be already wiser than we can be. Medicine is more modest but much more efficient.

Not only the severe retardation will be fighted effectively in the years to come but also a host of actually undefined conditions which impair mildly mental efficiency.

In this way genetics will play an eminent role at service of mental welfare of mankind. Suppression or repression of unfit or unconform ameliorates the statistics but not the heart of societies. Only an intimate union of heart and of reason will salvage someday human intelligence.