Test tube babies are babies

JÚrome Lejeune

Jerome Lejeune, M.D., Ph.D., is currently Professor of fundamental Genetics at the Faculte de Medecine Necker-Enfants Malades, Chief of the Department of Cytogenetics at the Hospital des Enfants Malades and Director of the Institut de Progenese, Paris.He is a member of various Academies of Sciences (Boston, London, Rome, Stockholm) and has received many awards for his work on human chromosomal diseases (Kennedy Award 1962, William Allan Memorial Award 1969).After the description of trisomy 21 (the cause of Down's syndrome), the first chromosomal disease discovered in man (1958 and 1959), and the first example of a translocation (1960), he described many chromosomal diseases (i.e., the Cri du chat syndrome due to a deletion of the short arm of chromosome 5 in 1963 and various partial, trisomies or monosomies like trisomy 9p, 8q, 8q-, 4p, etc.) in collaboration with workers in the Institut de Progenese (Dr. B. Dutrillaux, J. Lafourcade, and M.-O. Rethore).With H. Jerome he started metabolic studies in trisomy 21 which showed metabolic abnormalities in the kynurnine pathway (1960). In 1979, with P.M. Sinet and H. Jerome, he described an excess of activity of superoxide dismutase A in trisomic 21 children. It was the first demonstration of anincrease of enzyme, related to gene dosage effect.More recently the same authors described a correlation between the flutathione peroxidase activity level and the I.Q. of Down's syndrome children.After publishing a new model on the possible role of the one carbon cycle in the cause of mental retardation, especially in trisomy 21, he is currently working on clinical studies and metabolic trials. His work as a specialized consultant in the Hospital des Enfants Malades, for Down's syndrome, is extremely active (nearly 3,000 individual records).Besides his work on trisomy 21, he has made contributions to mathematical genetics, radiation genetics, chromosomal evolution of species and molecular biology.


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The feasibility of extracorporeal fecundation (also called in vitro fertilization) has experimentally confirmed our basic knowledge of the fundamentals of human reproduction. Besides this scientific achievement, the new techniques have opened possibilities which deserve careful investigation.

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The fundamentals of life

Life has a very, very long history but each individual has a very neat beginning: the moment of his or her conception. As it has been amply demonstrated (1) the whole biology of vertebrates teaches us that ancestors are united to their progeny by a continuous material link, for it is from the fertilization of the female cell (the ovum) by the male cell (the spermatozoon) that a new member of the species will emerge.

The material link is the thread-like molecule of DNA. This ribbon, roughly one metre long, is divided into segments (23 in man), and each segment is carefully coiled and packaged in the form of a little rod, clearly visible under the microscope: the chromosome.

As soon as the 23 maternal chromosomes encounter the 23 paternal chromosomes, the full genetic information, necessary and sufficient to spell out all the inborn qualities of the new individual, is gathered.

Exactly as the introduction of a minicassette inside a tape recorder will allow the "re-creation" of the symphony, the information included in the 46 chromosomes (the minicassettes of the symphony of life) will be deciphered by the machinery of the cytoplasm of the fertilized egg (the tape recorder), and the new being begins to express himself as soon as he has been conceived.

The fact that the baby will develop inside the womb for the next nine months is irrelevant at this point as in vitro fertilization has amply demonstrated.

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The technicalities of fecundation

In natural conditions, the ripe ovum is expelled from the ovary by rupture of the follicle and is recuperated by the fallopian tube. Inside this tube it migrates toward the uterus and en route, encounters the sperm which, alone among millions of others, will fertilize it.

At the end of the journey the fertilized egg, already dividing feverishly, and organizing itself in a minuscule embryo of 11/2 millimetres in diameter, accommodates itself inside the uterine mucosa (nidation) around 6 to 7 days after fertilization. There, firmly implanting itself, it will continue its growth, thanks to its placenta, until birth.

It is because normal fertilization occurs in a tube, with ovum and sperm floating freely inside the liquid, that test tube babies are possible. Indeed, in vitro fertilization uses a tube of glass instead of a tube of living tissue, but the process is, in other respects, identical.

Initially, artificial fertilization outside the maternal body was suggested to circumvent some cases of feminine sterility. It sometimes happens that fallopian tubes are blocked, most often as a sequel of sexually transmissible disease. In such cases, the spermatozoa cannot reach the egg nor the egg reach the uterus. To circumvent this blockage, the ripe egg is removed from the ovary by laparoscopy and put into a vessel containing an appropriate medium. The addition of sperm will lead to fertilization.

The early embryo will be delicately transferred a few days later, through the cervix of the uterus so that it can continue its development in the womb.

All this explains why Dr. Edwards and Dr. Steptoe could witness in vitro the very beginning of the exceedingly young Louise Brown, whom they replaced a few days later in the womb of her mother, Mrs. Brown. Thanks to the fundamentals of life already known, they were totally assured that this berry-looking being could not be a tumor nor an animal.

With hundreds of cases already described in various countries of the world we now have living witnesses for the first time in our own species: the early human embryo develops by its own virtue and it has incredible viability.

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Viability outside the womb

That the early human being is fully viable outside the maternal body is of no surprise but a confirmation of general principles.

Even in ordinary conditions, with a rather simple culture medium (the fluid of the fallopian tube), the early human embryo can continue its growth and development for days, maybe a week, and manage its own organisation; after one week, implantation is a necessity but the viability of the early human being is such that even the uterine mucosa is not a pre-requisite.

Up to two months, an embryo implanted inside the fallopian tube is fully efficient. In these extra-uterine pregnancies the tiny human being, smaller than a thumb is perfectly developed, the only danger being that its continuous growth would rupture dramatically the walls of the tube which cannot extend as a uterus would do. Even in extreme cases of extragenital pregnancies, when the foetus anchors itself in the abdominal cavity, directly on the peritoneum, the growth can be astonishingly normal for many months.

Protected by his life-capsule (the zona pellucida first and, later, the amniotic sac he constructs around himself) the early human being is just as viable and autonomous as an astronaut on the moon, refuelling with vital fluids as required from the mothership.

A purely artificial fluid supplier has not yet been invented. But if it ever possible, complete development outside the womb would belongs to himself. If the bottle (or test tube) could argue: "This baby baby is my property", nobody would believe the bottle.

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Time at a standstill

Careful refrigeration of living cells, protecting their precious molecular edifice, is of common use for long preservation. At very low temperature (-190c in liquid nitrogen) the vibrations of the atoms are restricted. Time is suspended, so to speak.

Frozen sperm can thus be kept for years. If thawed carefully they fully recover their potential as intrepid navigators. Sperm banks are a common tool of industrial breeding.

The same is true for early embryos. Some mouse embryos, deep frozen and thawed have managed, after implantation, to develop into perfectly normal mice. No such experiment has yet been reported in our own species; proposals are numerous although their ethical and scientific legitimacy is at least questionable.

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Twins at will

If the zona pellucida is split and the embryo is cleaved in two halves, each mass can be inserted in a separate zona pellucida.

Identical twins have thus been produced, in cattle and in sheep. Some have proposed to do the same in man. Their rationale is not "a production line" but the possibility of checking the genetic makeup of one of the twins. The scenario goes as follows: one twin is deep frozen, until further transfer, at the proper time, into a recipient uterus. The other twin is allowed to grow for a time and then examined for chromosomal constitution, normality of growth, and its various chemical properties. If this twin,the sacrificed twin, is declared O.K., the spared twin will then be transferred. If not, the spared would give full insurance for successful childbearing even for an at risk mother (for chromosomal or genetic disease).

Simple arithmetic (see annexe I) is not so promising or hopeful. A success rate of little more than a few per cent can hardly be expected. On average the egg donor would need to be tapped some twenty times :for each successful pregnancy: an extremely heavy burden, not to mention the 20 to 40 embryos who would not survive the whole experiment.

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Wombs for hire

If properly kept in "suspended animation" (there is no synchronisation of ovarian cycles in the population), an early embryo could be transferred at any suitable time into a recipient uterus. Many possible cases have been suggested:

For example, a widow could accommodate an embryo fathered long before by her deceased partner. A candidate, affected by an inheritable disease could receive an egg from a healthy donor. Or, a uterine foster-mother could be hired if the true mother could not carry the pregnancy for medical reasons. The possibility of surrogate mothers could enable some women even to avoid the inconvenience of pregnancy.

Surrogate pregnancy is a difficult issue. Should the foster mother be forced to give back the baby nine months later? Would she be denied the right to refuse termination of pregnancy if abortion were legal in her country? These questions are for lawyers. For the biologist, no matter what the alleged pretext, such practices would break the only assured link between generations. Up to now whatever the uncertainties of paternity, motherhood was an absolute certainty at delivery.

To be sure the technique works in cattle. But what is good for calves may not be good enough for children and mothers.

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Manipulated embryos

The full viability of the early being and its tenacity for life allow many experiments.

The cells of two different embryos can be mixed together; they thus result in a "compound" animal (called a chimera). Such experiments have been carried out with mice. To the best of our knowledge, no compound mouse has yet been obtained from more than three cell lines mixed together (2). This fact recalls that during the first cleavages of the fertilized egg (occurring within minutes of conception), there is an odd stage of three primordial cells. It maybe that this threecell stage has something to do with the individuation process.

It must be remembered that normally the zona pellucida prevents these admixtures: in a sense this bag ensures our early private life. It is an open possibility that normally the human embryo emerges from its zona pellucida only when its biological individuality is so strongly established that a chimeric accident is no longer to be feared.

But even if mixing must be restricted to two or three cell-lines, what about an "artistic" embryo, an "athletic" embryo and a "scientific" one, fused together?

Would not that create a kind of superman?

Or, if DNA manipulation comes in: what about embryos receiving special sequences, producing exceptional endowments?

These fictional experiments are not worthy of discussion. These nursery tales for grown-ups should be totally rejected: to devise a man wiser than we are, we should be already wiser, than we can be.

As for the proposals of manipulating embryos in order to produce spare parts for repairing children or adults, they are so far-fetched that no critical analysis can be made. Conceivably grafts of stem cells could be of theoretical interest; but they are already catered for from voluntary donors (bone marrow graft for example). In any case which tissues are going to develop into particular organs are not yet detectable in the pre-implanted embryo.

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A sex choice

As BRUNGS Stated succinctly about the advent of generalised contraception and, later, of efficient in vitro fertilization: we have gone "from sex without babies, to babies without sex".

But the sex of the baby still matters.

The preference for a "King" means a son for a first child and often for the second. The same applies to the man in the street; and even for suffragettes and, now, the feminists. All opinion polls show the same results: if free choice were given, a formidable excess of males would result!

Thank God no sieve is available to select preferentially the male sperm (carriers of the Y chromosome). Thus pre-determining the sex of the embryo is at present completely out of reach.

If an acceptable technique were someday to be available, the State could not remain indifferent before such a predictable disaster: woman-deprived population! In order not to infringe upon free choice and not to favour anyone, enormous computers would process the demands, producing optimal decisions. As demonstrated by GROUCHY (2) the best algorithm is not too cumbersome to calculate: toss a coin as before!

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The real question

But do we ask the real question? If our only goal is to help women who cannot conceive because of tubal difficulties, have we chosen the right course?

Let us return to technicalities. If the early embryo is really not experimental material to be split, mixed, manipulated or anything else, what is so interesting about this excursion of a few days into the outside world?

Dr. CRAFT and his colleagues (4) have already shown that the fertilized ovum can be implanted right away in the womb. Could we not get even closer to the actual physiological process? Possibly the egg could be placed in the uterus during the actual laparoscopy, the sperm being already supplied by normal intercourse?

Why not study more closely the fluid of the fallopian tube? Would it not be the best medium for early development?

Research workers would be wise to explore such new avenues instead of following automatically the long detour of in vitro fertilization.

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The future of medicine

Arguments have been put forward repeatedly that in vitro fertilization would help in discovering the cure of a whole array of disease, even breast cancer! But all available evidence points towards other directions of research as shown-by three recent examples:

Among the genetic scourges afflicting humanity, mental retardation is the most inhuman. It deprives the afflicted of one of the most precious aspects of our heritage: the full power of thought.

Some ten per cent of the mentally retarded show a peculiar fragility of the X chromosome. Numerous examinations have shown that this fragility can be healed if the cells are cultivated in a medium containing various chemicals (5); a simple vitamin, folic acid and its derivatives, is especially efficient. If it is added to the regimen of these patients their X chromosome gap seems to disappear as well. Moreover, preliminary clinical trials show that their mental status can be partially ameliorated (6).

Actual cure of the disease has not yet been discovered, but it is the first time that a chromosomal disease and its deleterious consequences have been successfully attacked - and, this, without resorting at all to "science fiction" devices.

Another terrible disease resulting from imperfect closure of the neural tube in embryonic life, seems also to be amenable to vitamin therapy. As demonstrated by SMITHELLS et al (7) and confirmed by LAURENCE et al (8) vitamin therapy, including folic acid, given at the appropriate time to the mother at risk, diminishes drastically the frequency of spina bifida. Here again no experiment on the embryo was required.

A third advance has been made in genetically transmitted anaemias.

During life in utero and after, haemoglobin is produced by an array of different genes working in succession: the first during the embryonic stage; the second in the foetus; and the third in the whole adult life. If this last gene is mutated, an abnormal haemoglobin is made (as in thalassemias or in sickle-cell anaemia).

It has been discovered that the silent genes can be reactivated by a special chemical (azacytidine). LEY et al (9) took advantage of this property with the result that patients suffering from abnormal adulttype haemoglobin started to produce again their normal foetal-type. This type of rejuvenation could be of great significance for further therapy, without involving any manipulation of embryos or the foetus.

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Aldous Huxley, Wolfgang Goethe and the newspaperman

A last question remains: why is in vitro fertilization such a fascinating issue? Although the Brave New World is often quoted in this context, it is probably not the industrial production line of identical twins which is the key point. At least Aldous Huxley himself stressed another phenomenon: in his technological society, liberated of every tabco, all obscene words were in the current language. Nevertheless, editors were obliged to reprint all literature in order to expurgate it of the only incongruity which could not be pronounced, and should not even be read and was to be replaced by suspension points: the word "mother".

Motherhood, a total obscenity: such an inversion of values is a supreme danger, Aldous Huxley warned us.

But another writer, one of the greatest poets, had already seen much further, more than a century and a half ago. In Faust (Part I), Goethe told of the tragic abandonment of the beloved, seduced and pregnant. But in Faust (Part II) the vision goes even deeper. After his pact with Mephistopheles, Faust returns to his old laboratory with his diabolic companion. They watch the successor of Faust producing an homonculus inside an alchemic vessel! The tiny creature escapes and floats in the air around the head of Doctor Faust who loses his mind but not his imagination guided as he is by this strange in vitro baby.

After an impossible love affair with the ghost of Helen of Troy, Faust fially accomplishes his goal. He builds an empire, a fully technical society, with the magical help of Mephisto. At the very end he gives his last orders: to silence the little church bell, the only one still ringingin his whole empire, and to destroy the cabin in which Philemon and Baucis remain, the parragons of human love.

And, when silence comes, when Mephisto returns after having burned the elderly lovers in their cabin, then, implacably, sorrow invades the heart of Faust.

Poets are above science; they see further and feel far more than technicians could ever grasp. In such important matters it could be profitable for scientists and legislators to re-read some of the great masters.

But maybe they could rely just as well on other writers, far more accessible to them - indeed, living among them. I mean newspapermen.

They also do not practise science but witness it from outside, and their judgment is not to be taken lightly. They know that in vitro fertilization fascinates their readers and one journalist understood why. Trying to convey all the significance of what was going on he coined the term: "test tube baby". Sure enough scientists objected (they preferred to overlook it) but the journalist knew better.

Indeed, if there is a growing repugnance against any exploitation of the early human embryo, if people are beginning to feel that experimenters must have total respect for these marvelous young human beings, it is for a scientific reason: a newsman discovered in a stroke of intuitive genius - test tube babies are babies.


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bibliographie

(1) LEJEUNE J. On the beginning of life. Testimony before the Senate of the United States of America. Subcommittee on Separation of Powers. April 13, 1981.

(2) GROUCHY J. de. Jumeaux, mosaiques, Chimeres et autres aleas de la fecondation humaine. MEDSI Edit. Paris 1980.

(3) GROUCHY J. de. Lesnouveaux Pygmalions. Gauthier Villars Edit. Paris 1973.

(4) CRAFT, McLEOD F., GREEN S., DJAHANBALHCH O., BERNARD A., TWIGG H., et SMITH W., 1982 - Birth following oocyte and sperm transfer to the uterus, Lancet ii, 1982, 773.

(5) SUTHERLAND, G.R. 1979. Heritable fragile sites on Human chromosomes I. Factors affecting expression in lymphocyte culture. Am. J. Hum. Genet. 31, 125-135.

(6) LEJEUNE J. Le metabolisme des monocarbones et le syndrome de l'X fragile. Bull. Acad. Nat. Med. 1981, 165.

(7) SMITHELLS R.W., SHEPPARD S., SCHORAH C.J., SELLE M.J., NEVIN N.C., HARRIS R., READ A.P. et FIELDINK D.W. Possible Prevention of neural tube defects by periconceptional vitamin supplementation. Lancet i, 339-340, 1980.

(8) LAURENCE K.M., JAMES N., MILLER R.H., TENNANT G.B. et CAMPBELL H. 1981. Double-blind randomised controlled trial on folate treatment before conception to prevent recurrence of neural-tube defects. Brit. Med. J. 282, 1509-1511.

(9) LEY T.J., DESIMONE J., ANAGNOV N.P., KELLER G.H., HUMPHRIES R.K., TURNER P.H., YOUNG N.S., HELLER P., NIENHUIS A.W. 1982. 5-Azacytindine selectively increases 8-globulin synthesis in a patient with B + thalassemia. New Engl. J. Medicine 307, 1475-1469.