Prevention techniques for congenital disabilities : quo vadis ?

J. Lejeune



The fundamentals of life

Life has a very, very long history, but each of us has a very precise beginning : the moment of the conception. The progeny and the parents are constantly, united by a material link, the threadlike molecule of DNA, upon which the complete genetic information is written in a fantastically miniaturized language.

On the head of a spermatozoon, there is a one meter length of DNA, cut in 23 pieces. Each segment is very precisely coiled to form little rods visible With an ordinary microscope : the chromosomes.

As soon as the sperm has perforated the "zona pellucida", the plastic bag inside which the ovum is wrapped, the membrane becomes suddenly impenetrable to any other sperm. In purely operational terms, it can be stated that as soon as the 23 paternal chromosomes carried by the sperm are put in the same bag as the 23 maternal chromosomes (carried by the ovum), the total information necessary and sufficient to dictate the genetic make-up of the new human being is gathered. Not a theoretical or a potential human type, but the very human being we will later call Peter, Paul or Magdalene.

Exactly as introducing a mini-cassette inside a tape recorder will allow the playingof a symphony, the music of the life is played by the machinery of the cytoplasm, and the new human begins to express himself as soon as he has been conceived.

Soul and body or spirit and matter are so intricately interwoven at the beginning of life that we use the same Word, conception, to describe the process by which an idea, a concept, comes into our mind, and to define the genetic process by which a new being, a conceptus, comes to life.

Protected in its life capsule (the zona pellucida first, then the amniotic bag he constructs around himself) the early human being is just as viable and autonomous as a cosmonaut on the moon : refueling with vital fluids is required from the mother vessel. No artificial fluid supplier has yet been invented ; shelter and nurture by the mother organism are absolutely required.


Congenital abnormalities

Two types of misfortunes, inborn or acquired, can hamper the future. At the very beginning, an unequitable patrimony could darken the destiny.

A misspelling of the genetic message (a "mutation" like phenylketonuria) or a mistake in the binding of the volumes of the tables of the law of life (a chromosomal aberration like trisomy 21) could curb the embryological process or modify chemical reactions. Affected in his flesh and/or in his mind, the child will suffer of a physical and/or mental impairment.

Secondarily, because of the length (9 months) and of the complexity of this construction period, any assault can be deleterious (be it a viral infection, a chemical aggression or an inadequate nutrients supply). A child concieved per fectly healthy, can thus acquire physical or mental disalibilities in utero : post rubeolic malformations or neural tube defects like Spina bifida or anen-kephaly.

It follows that if a child is found carrier of an inborn anomaly, or of a developmental difficulty, its destiny can be predicted with an appreciable accuracy.


Prevention or destruction : quo vadis ?

Acquired abnormalities can be prevented : vaccination of young girls against rubella will protect the future babies and in the case of neural tube defects, the remarkable achievements of Smithells (1) has shown that folic acid given to the would be mother could diminish by a factor of ten, the risk of this disastrous malformation of the nervous systems.

On the same way, some exceptional cases of inborn errors can be adequatly managed in utero. For example, Methyl cobalamin deficiency can be compensated by vitaminotherapy of the pregnant mother (2) or, rhesus foeto maternal incompatibility can be prevented by "vaccination" of an at risk mother or treated by exsanguino transfusion of the baby even in the womb.

But in the overwhelming majority of cases, no efficient protective answer is available.

Nowaday, amniocentesis, chorionic biopsy, or advanced imagery allow early detection of various afflictions, but the avowed purpose of these prenatal diagnosis is to eliminate by abortion the affected babies. Even in case of twin pregnancies, some have selectively killed the affected twin in utero (3) and in case of unwanted quintuplet pregnancy, have even killed by cardiac puncture three out of the five foetuses (4).

Health by death is a desperate mockery. The complete history of medicine is on hand to show that those who delivered humanity from plague and rabies were not those who burned the plague stricken alive in their houses or suffocated rabid patients between two mattresses. The only possible victory of medicine is over the disease, not over the patient.

Some technicians are even requesting the right to experiment on human embryos produced by in vitro fertilization. They say this will help them to understand, to prevent, and possibly cure very terrible genetic disabilities like hemophilia, muscular dystrophy, cystic fibrosis or Down's syndrome.

Three years ago I had the honor of explaining to members of the British Parliament that research on those diseases could not be performed at all on human embryos less than 14 days old for a very decisive reason : at this stage of development, the relevant organs (brain for mental retardation, pancreas for cystic fibrosis, muscle for muscular dystrophy, or blood-forming organs for hemophilia) are not yet developed.

Considered as a "french influence in Britain" (5) such a matter of fact statement was severly criticized by the promoters of experiments on human embryos. An appeal to embryologists (6) requested protocols showing convincingly that human embryos (no animal embryos) were absolutly requested.

Nearly there years later, no such protocol has been published !

On the contrary an advanced country, especially aware of the dangers of indulging experimentation on man, West Germany, is considering a law protecting the early human beings from any exploitation (7).

The very question is not to express a wish full statement that "embryo research may, in due course, enhance the same ideal, perhaps by helping to rid people of undignifying genetic diseases" (8) but to realise that we "are a long way from curing anyone of a genetic disease, but have already begun ridding ourselves of PEOPLE, with what we consider "undignifying genetic diseases", through abortion and euthanasia" (9).

Thöse recent quotations show how appropriate it is to ask Quo Vadis : where areth thou going ?

Should we accept the repeated leitmotiv that a full respect of the human nature is an out of fashion taboo and, frankly speaking, that moral is an impediment to discovery ? The very recent developments of molecular biology are confirming again and again that no good science has ever been builded on contempt of human dignity.

During the last three years, thanks to the work of many different researchers in many countries, the genes of cystic fibrosis (10) and of Duchenne's muscular dystrophy (11) have been found and cloned, as well as those of Huntington's Chorea (12) and of retinoblastoma (13). Even the specific protein of muscular dystrophy the "dystrophin" is now identified and analysed (14). For hemophilia, the special coagulation factor is now manufactured by manipulated bacterias so that patients can be treated with a pure product without any risk of transmission of AIDS through contaminated blood !

All these successes since 1985 have been obtained without endangering human embryos at all. And none of the experiments were in contradiction with the absolute respect of each and every human being, from conception to natural death, which has always been the guideline of civilized scientists.

In this context, it is worth quoting the solemn declaration of 15 research workers of the Max Planck Institute "The abuse of these techniques through experiments with human embryos (or pre-embryos, if one considers a preimplantation embryo not to be an embryo) must be condemned by the scientific community" (15).

It is conforting that scientists living in a country in which the denatured biology at the nazis was once the legal doctrine, are thus restoring the dignity of biology as an honest servant of true medicine.


Toward a rehabilitation medicine

Two ways are broadly open : First the dechiphering of the abnormal gene products (like the dystrophin already quoted) will allow to understand their action and to find means of alleviating and even totally preventing their deleterious effects. This will be curative medicine of a very classical type even if highly sophisticated.

The second possibility could be, a direct correction of the bad gene. For instance a kind of "Magic Bullet" (a modified virus may be) could knock out the wrong genetic information and replace it by a correct segment of DNA. Although still very remote, this prospect is maybe not as far fetched as it could seem today.

These two procedures can be clearly envisaged for congenital abnormalities due to one mistake. But what about chromosomal errors where many genes (hundreds, thousands) are in fault or in excess ? The example of Down Syndrome to which I am particularly devoted will allow a short discussion of the state of affairs.

In this type of mental retardation affected children carry three chromosomes 21 instead of two normally. This trisomy 21 provokes a kind of "overdose" of genetic information.

The situation is roughly comparable to a car with a four cylinder engine mounted by mistake with fire spark plugs ! Sure enough the motor would not run smoothly. A good car repairman, instead of throwing it away, (as an abo tionist would do), would delicately disconnect the extra spark plug and thus put the function back to normal.

We do not know yet how to unplug an extra chromosome, but nature does. She unplugs the extra X chromosomes when necessary. Maybe some day we will learn how to do it and apply the trick to the extra chromosome 21, responsible for the trisomy, the cause of Down's syndrome. Pending this "tour de force", yet to be invented, we can continue deciphering the genetic content of this chromosome. Already eight genes and multiple unnamed protein spots and scores of anonymous DNA segments are known. It is reasonable to suppose that in less than 10 years, the whole DNA of this chromosome will be unraveled. In the mean time, we can try to understand why and how the excess of the genes impair the functionning of nerves cells and prevent the full development of intellectual power. To keep the analogy with automobiles, we can look for some regulation of the "carburation" of the motor, so to speak.

It is already established that trisomic 21 children are more sensitive than normals to methotrexate (16). This anti-cancer drug interrupts the transport system of monocarbons, the small building blocks of important molecular edifices in the brain. This sensitivity can be demonstrated (17) in blood cells cultivated in vitro, and numerous other modifications of the culture medium are now feasible (18).

As curious as it could look, in vitro experimentation on cultivated cells, taken from a few drop of blood can allow a fine analysis of the genetical and biochemical troubles which provoke mental retardation or even psychiatric disorders. The mental retardation linked to the fragile-X condition, or to hypothyroïdy are other examples of this type of investigations (19)(20).

Without going too deep in technical matters it can be predicted that various psychiatric syndromes (autism, Alzheimer-like deterioration) will be soon be studied experimentally in vitro, thank to these new procedures.

That is not to say that the destiny of these cheerful children will soon be allieviated although some medication trials are already attempted with interesting results (21)(22)(23)(24).

On the contrary, it means that important discoveries are just beginning and that respect for human nature does not impair research but stimulates it. The promoters of selective abortion, or of exploitation of human embryos were mistaken offering us this cruel dilemma : either you take part in this search and destroy mission and you accept the massacre of the innocents, or you refuse to help the families affected by incurable children and you wash your hands of their sorrow. No, medicine is not forced to choose between playing Herod or Pontius Pilate. It has to fight against the disease, not against the patient.

Nevertheless, in name of the technical progress, especially appointed "ethical" committees will possibly continue to try to blurr the moral judgment. But their contradictory oracles will never fully exorcize the sorrow, for a decisive reason : Technology is cumulative, wisdom is not.

When man himself is at stake the utmost wisdom is a moral principle, very simple and clear : "What you have done to the smallest of mine you have done it into Me".

If doctors always remember this word, the most sophisticated technique will remain the honest servant of rehabilitation medicine ; but if they forget it, then a denatured biology could never be rehabilitated.



(1) Smithells R. W., Nevin N.C., Seller M. J., Sheppard S., Harris R., Read A., Fielding D.W., Walker S., Schorah C.J., Wild J. Further experience of vitamin supplementation for prevention of neural tube defect recurrences. Lancet i, 1983, 1027-1031.

(2) Rosenblatt D.S., Cooper B.A., Scmutz S.N., Zaleski W.A., Casezy R.E. Prenatal vitamin B12 therapy of a foetus with methycobalamin deficiency (Cobalamin E Disease). Lancet i, 1985, 1127-1129.

(3) Berg D., Baumgartner M., Doring K. Selective abortion of a twin with trisomy 21 via sectio parva in 23 pregnancy week and subsequent spontaneous birth of the healtly second twin. Geburtshilfe Frauenheil KD 1984, 44, 563-565.

(4) Kanhai H.H.H., Van Rissel E.J.C., Meerman R.J., Gravenhorst J. Selective termination in quintuplet pregnancy during first trimester. Lancet i, 1986, 1447.

(5) Walgate R. French influence in Britain. Nature 1985, 313, pp. 618.

(6) Editorial, Nature, An appeal to embryologist. Nature 1985, 314, pp. 11.

(7) Dickman S. Embryo research ban causes ructions in West Germany. Nature 1988, 333, 791.

(8) Editorial. Criminalizing research. Nature 1988, 333, pp. 787.

(9) Cochran K.W.M. German angle. Nature 1988, 334, pp. 560.

(10) Beaudet et coll. Linkage of cystic fibrosis to two tightly linked DNA markers : joint report of a collaborative study. Am. J. Hum. Genet. 1986, 39, 681-693.

(11) Monaco A.P., Neve R.L., Colletti-Feener C., Bertelson C.J., Kurnit D.M., Kunkel L.M. Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene. Nature 323, 646-650.

(12).Landegent J.E., Jansen in de Wal N., Fisser-Groan Y.M., Bakker E., Van Der Ploeg M., Mearson P.L. Fine mapping of the Huntington disease linked D4S10 locus by non-radioactive in situ hybridization. Hum. Genet. 1986, 73, 354-357.

(13) Friend S.J., Bernards R., Rogel J.S., Weinberg R.A., Rapaport J.M., Albert D.M., Dryja T.P. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986, 323, 643-646.

(14) Editorial : Dystrophin. Lancet ii, 1988, 429-430.

(15) Balling R., Chowdhury K., Deutsch U., Dietrich S., Drescher U., Henseling U., Jostes B., Kristjansson G.I., Demaeyer T., Püschel A., Schöler H., Siekhaus D., Theuring F., Walther C., Zimmer A. Moratorium call. Nature 1988, 334, 560.

(16) Peeters M., Poon A. Down syndrome and leukemia : unusual clinical aspects and unexpected methotrexate toxicity. Eur. J. Pediatr. 1987, 146, 416-422.

(17) Lejeune J., Rethoré M.O., de Blois M.C., Maunoury-Burolla C., Mir M., Nicolle L., Borowy F., Borghi E., Recan D. Métabolisme des monocarbones et trisomie 21 : sensibilité au méthotrexate. Ann. Génét. 1986, 29, 16-19.

(18) Peeters M., Borghi E., Vasquez M.P., Lejeune J. Methotrexate toxicity in Down syndrome ; investigation of thymidylate synthetase and thymidine kinase patheways. Exp. Cell Res. 1988, (under press)

(19) Lejeune J. Le métabolisme des monocarbones et la débilité mentale. J. Lejeune Edit. Masson Paris 1983, pp. 4-18.

(20) Lejeune J. Research on pathogeny of mental retardation in trisomy 21. in : Aspect of the uses of Genetic Engineering. Pont. Acad. Sci. (Roma) 1987, Commentarii III, 31, 1-18.

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(22) Lejeune J., Rethoré M.O., de Blois M.C., Peeters M. Psychose infantile, syndrome pseudo Alzheimer et trisomie 21. Essai de medication par l'acide folinique : rapport préliminaire. Therapie 1988, (under press)

(23) Hobbs J.R. Displacement bone-marrow transplantation and immunoprophylaxis to treat some genetic diseases. Bone-Marrow transplantation 1, 1986, 333-35

(24) Naruse H., Mayashi T., Takesada M., Nakane A., Yamazaki K., Noguchi T., Watanabe Y., Hayaishi O. Therapeutic effet of tetrahydrobiopterin in infantile autism. Proc. Japan Acad. 1987, 63 Ser. B, 231-233.