The Lejeune Foundation supports more than 60 international research programs on genetic diseases affecting intelligence, chief among them Trisomy 21. One program, launched in 2004, investigates how to inhibit the excess CBS enzyme, which partly accounts for the mental retardation in Trisomy 21. Research is advancing in the identification of a molecule capable of inhibiting the CBS enzyme.
In the early 1970s, an International Congress on Health convened in New York, where Professor Lejeune—a French physician and researcher at Necker Hospital in Paris—presented to the scientific world his discovery of Trisomy 21, made in 1959, and his hypothesis that it was linked to Down syndrome, or mongolism. This syndrome is marked by congenital mental deficiency and remains the leading cause of mental deficiency worldwide.
With his discovery, Professor Lejeune initiated modern genetics in the biomedical field, and sparked broad and increasingly profound debate. He was convinced that it would soon become possible to cure mental illnesses of genetic origin, just as other diseases once thought untreatable had become curable. To that end, he pursued his research with tenacity, standing in clear opposition to much of the scientific community that advocated abortion.
At this point, a brief discussion of DNA will help clarify what has been said above.
DNA is an extremely fine filamentous macromolecule, contained in the nucleus of every cell and measuring about one meter in length. This molecule, invisible under an optical microscope, was identified using electron microscopy (magnification up to 750,000 times and beyond), separated and isolated from the cell using refined and specific techniques, and subsequently analyzed with increasing precision as molecular biology techniques were perfected and multiple subcellular structures revealed.
Along the DNA filament, scientists identified molecular sequences called genes, which direct and determine the synthesis of proteins within the cell: structural proteins necessary to maintain cells in their proper form, and functional proteins that enable cells to carry out their specific role in the body's economy.
As noted above, the DNA filament is invisible under an optical microscope, but for some time special formations had been known and described that appeared evident in fixed and stained cells, taking on particular shapes and arrangements during the phases of cell replication: chromosomes. It was thus possible to establish that each human cell contains 23 chromosomes, each represented twice. The total number of chromosomes in the human species is therefore 46, or 23 pairs, with each pair consisting of two identical chromosomes. They were classified with numbering from 1 to 23. Molecular biology data made it possible to establish that chromosomes represent the collection, in 23 separate and double coils, of the one-meter DNA filament tightly wound so that it can be stained and made visible under an optical microscope.
Each species has its own peculiar number and appearance of chromosomes.
At the time of Professor Lejeune's discovery, the molecular techniques needed to isolate and purify specific genes had not yet been developed. His tenacious dream—that the gene for the CBS enzyme (cystathionine β-synthase), which he had hypothesized before 1975 to be located on chromosome 21—seemed a chimera, impossible to prove and bearing no relationship to Trisomy 21.
In 1985, however, as molecular biology research continued, scientists determined that:
- in the normal individual, the CBS gene is present on chromosome 21 in 2 copies
- in Trisomy 21 (where 3 chromosome 21s are present), this gene exists in 3 copies.
It is now thought that excess production of the CBS enzyme may play a role in the onset of mental deficiency.
Following this research direction, the Lejeune Foundation committed itself to identifying a possible inhibitor of the excess CBS enzyme produced.
To this end, it was first necessary to have access to a vast array of molecules to screen. By September 2008, several molecules active in inhibiting the CBS enzyme had been identified.
One, Hit-1, appeared most promising but proved toxic. To study its mechanism of action requires:
- in vitro cellular models (currently under development)
- appropriately prepared animal models (mice).
Transgenic mice (mice with their own genes removed and/or genes from other species introduced) are already in experimental phases, carrying:
- Trisomy 17
- Three CBS genes
- A portion of chromosome 21 on the chromosome
Crystallization of the CBS-Hit-1 complex is in experimental phase to see where Hit-1 attaches in inhibiting CBS. The synthesis of analogous molecules is envisioned to find a molecule similar to Hit-1 that attaches to CBS in the same place as Hit-1 but is not toxic. The most suitable molecule is being selected for in vitro assays on cellular models and in vivo assays on animals.
The Lejeune Foundation's commitment is, as can be seen, a colossal undertaking requiring at least 10 to 15 years of unrelenting work.
The future treatment, if made possible, will transform perspectives on Trisomy 21 and on all people affected by genetic disease, offering everyone hope of a cure. Achieving this requires help—and time is of the essence.
Now that several molecules have been obtained as possible CBS inhibitors, we can appreciate the ground already covered, especially in 2009, the fiftieth anniversary of Professor Lejeune's discovery of Trisomy 21.
Yet many difficult steps remain ahead. All are therefore called upon to contribute urgently to this vital project.
It is worth recalling the moving and tragic letter from C. Lejeune: Life Is a Challenge—Cantagalli, Siena 2008, presented in Ombre e Luci n° 104—which Professor Lejeune sent to his wife after the International Congress mentioned at the opening. He had come to realize that he stood against the current; he understood he would never win the Nobel Prize despite his fundamental discovery, because in every debate he had vigorously defended life, God's gift, even for those deemed worthy of elimination because of disability. As a true physician and true believer, he knew one must never lose faith in the power of human reason, created in God's image and likeness, to resolve and cure even the gravest and most mysterious diseases.
Bound to John Paul II by profound esteem and friendship, the pontiff made him the first president of the Pontifical Academy for Life, instituted in February 1991.
On April 25, 2007, with the opening of his cause for beatification, Professor Lejeune was declared a Servant of God.
L.B., 2009
The Jerome Lejeune Foundation funds only research that respects the human being. The foundation does not support projects that use human embryos or fetuses as research material.
Those wishing to contribute to research of such great importance may direct donations to: Fondazione Lejeune IBAN FR76 1020 7000 4104 0410 2908 063 SWIFT CCBP FRPP MTG